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Harshita, Harish V, Upendra SL, Mohd S, Singh SK, Agrawal P, Vishwas S, Dua K. Next-Gen Cancer Treatment: Nanotechnology-Driven siRNA Delivery Solutions. Assay Drug Dev Technol 2025. [PMID: 40080397 DOI: 10.1089/adt.2024.121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/15/2025] Open
Abstract
RNA interference through small interfering RNA (siRNA) has shown great promise as a potential cancer treatment strategy in recent years. However, the delivery of siRNA to target cancer cells efficiently remains a significant challenge. This review aims to highlight the recent advances in nanotechnology-enabled siRNA delivery for cancer treatment, bridging the gap between bench research and clinical application. A comprehensive literature search was conducted to identify recent studies focused on the utilization of nanotechnology for siRNA delivery in cancer treatment. Key databases, including PubMed, Scopus, and Web of Science, were used, and relevant articles were screened. Several nanotechnology-based platforms for siRNA delivery have emerged in recent years, providing enhanced selectivity, improved stability, and controlled release profiles. The primary types of nanocarriers discussed include lipid-based nanoparticles, inorganic nanoparticles, polymeric nanoparticles, and exosomes. Nanotechnology-based siRNA delivery systems represent a promising avenue for cancer treatment. Although significant progress has been made in preclinical studies, translating these findings to clinical applications poses several challenges, including scale-up production, safety, and targeted delivery. Nevertheless, the recent developments in this field hold great promise in revolutionizing cancer therapy, providing hope for more effective and personalized treatment options in the future.
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Affiliation(s)
- Harshita
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Vancha Harish
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sakshi Lad Upendra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sharfuddin Mohd
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Pooja Agrawal
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, Australia
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
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2
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Idres YM, Idris A, Gao W. Preclinical testing of antiviral siRNA therapeutics delivered in lipid nanoparticles in animal models - a comprehensive review. Drug Deliv Transl Res 2025:10.1007/s13346-025-01815-x. [PMID: 40000558 DOI: 10.1007/s13346-025-01815-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2025] [Indexed: 02/27/2025]
Abstract
The advent of RNA interference (RNAi) technology through the use of short-interfering RNAs (siRNAs) represents a paradigm shift in the fight against viral infections. siRNAs, with their ability to directly target and silence specific posttranscriptional genes, offer a novel mechanism of action distinct from that of traditional pharmacotherapeutics. This review delves into the growing field of siRNA therapeutics against viral infections, highlighting their critical role in contemporary antiviral strategies. Importantly, this review will solely focus on the use of lipid nanoparticles (LNPs) as the ideal antiviral siRNA delivery agent for use in vivo. We discuss the challenges of siRNA delivery and how LNPs have emerged as a pivotal solution to enhance antiviral efficacy. Specifically, this review focuses on work that have preclinically tested LNP formulated siRNA on virus infection animal models. Since the COVID-19 pandemic, we have witnessed a resurgence in the field of RNA-based therapies, including siRNAs against viruses including, SARS-CoV-2. Notably, the critical importance of LNPs as the ideal carrier for precious 'RNA cargo' can no longer be ignored with the advent of mRNA-LNP based COVID-19 vaccines. siRNA-based therapeutics represents an emerging class of anti-infective drugs with a foreseeable future as suitable antiviral agents.
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Affiliation(s)
- Yusuf M Idres
- Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Adi Idris
- Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Wenqing Gao
- Centre for Immunology and Infection Control, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
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3
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Choi GW, Kim JH, Kang DW, Cho HY. A journey into siRNA therapeutics development: A focus on Pharmacokinetics and Pharmacodynamics. Eur J Pharm Sci 2025; 205:106981. [PMID: 39643127 DOI: 10.1016/j.ejps.2024.106981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
siRNA therapeutics are emerging novel modalities targeting highly specific mRNA via RNA interference mechanism. Its unique pharmacokinetics (PKs) and pharmacodynamics (PDs) are significant challenges for clinical use. Furthermore, naked siRNA is a highly soluble macromolecule with a negative charge, making plasma membrane penetration a significant hurdle. It is also vulnerable to nuclease degradation. Therefore, advanced formulation technologies, such as lipid nanoparticles and N-acetylgalactosamine conjugation, have been developed and are now used in clinical practice to enhance target organ delivery and stability. The innate complex biological mechanisms of siRNA, along with its formulation, are major determinants of the PK/PD characteristics of siRNA products. To systematically and quantitatively understand these characteristics, it is essential to develop and utilize quantitative PK/PD models for siRNA therapeutics. In this review, the effects of formulation on the PKs and PK/PD models of approved siRNA products were presented, highlighting the importance of selecting appropriate biomarkers and understanding formulation, PKs, and PDs for quantitative interpreting the relationship between plasma concentration, organ concentration, biomarkers, and efficacy.
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Affiliation(s)
- Go-Wun Choi
- College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea
| | - Ju Hee Kim
- College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea
| | - Dong Wook Kang
- College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea
| | - Hea-Young Cho
- College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Republic of Korea.
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4
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Askarizadeh A, Vahdat-Lasemi F, Karav S, Kesharwani P, Sahebkar A. Lipid nanoparticle-based delivery of small interfering RNAs: New possibilities in the treatment of diverse diseases. Eur Polym J 2025; 223:113624. [DOI: 10.1016/j.eurpolymj.2024.113624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Alnefaie GO. A review of the complex interplay between chemoresistance and lncRNAs in lung cancer. J Transl Med 2024; 22:1109. [PMID: 39639388 PMCID: PMC11619437 DOI: 10.1186/s12967-024-05877-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 11/11/2024] [Indexed: 12/07/2024] Open
Abstract
Lung Cancer (LC) is characterized by chemoresistance, which poses a significant clinical challenge and results in a poor prognosis for patients. Long non-coding RNAs (lncRNAs) have recently gained recognition as crucial mediators of chemoresistance in LC. Through the regulation of key cellular processes, these molecules play important roles in the progression of LC and response to therapy. The mechanisms by which lncRNAs affect chemoresistance include the modulation of gene expression, chromatin structure, microRNA interactions, and signaling pathways. Exosomes have emerged as key mediators of lncRNA-driven chemoresistance, facilitating the transfer of resistance-associated lncRNAs between cancer cells and contributing to tumor development. Consequently, exosomal lncRNAs may serve as biomarkers and therapeutic targets for the treatment of LC. Therapeutic strategies targeting lncRNAs offer novel approaches to circumvent chemoresistance. Different approaches, including RNA interference (RNAi) and antisense oligonucleotides (ASOs), are available to degrade lncRNAs or alter their function. ASO-based therapies are effective at reducing lncRNA expression levels, increasing chemotherapy sensitivity, and improving clinical outcomes. The use of these strategies can facilitate the development of targeted interventions designed to disrupt lncRNA-mediated mechanisms of chemoresistance. An important aspect of this review is the discussion of the complex relationship between lncRNAs and drug resistance in LC, particularly through exosomal pathways, and the development of innovative therapeutic strategies to enhance drug efficacy by targeting lncRNAs. The development of new pathways and interventions for treating LC holds promise in overcoming this resistance.
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Affiliation(s)
- Ghaliah Obaid Alnefaie
- Department of Pathology, College of Medicine, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia.
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6
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Nguyen L, Nguyen TT, Kim JY, Jeong JH. Advanced siRNA delivery in combating hepatitis B virus: mechanistic insights and recent updates. J Nanobiotechnology 2024; 22:745. [PMID: 39616384 PMCID: PMC11608496 DOI: 10.1186/s12951-024-03004-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/09/2024] [Indexed: 12/06/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a major health problem, causing thousands of deaths each year worldwide. Although current medications can often inhibit viral replication and reduce the risk of liver carcinoma, several obstacles still hinder their effectiveness. These include viral resistance, prolonged treatment duration, and low efficacy in clearing viral antigens. To address these challenges in current HBV treatment, numerous approaches have been developed with remarkable success. Among these strategies, small-interfering RNA (siRNA) stands out as one of the most promising therapies for hepatitis B. However, naked siRNAs are vulnerable to enzymatic digestion, easily eliminated by renal filtration, and unable to cross the cell membrane due to their large, anionic structure. Therefore, effective delivery systems are required to protect siRNAs and maintain their functionality. In this review, we have discussed the promises of siRNA therapy in treating HBV, milestones in their delivery systems, and products that have entered clinical trials. Finally, we have outlined the future perspectives of siRNA-based therapy for HBV treatment.
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Affiliation(s)
- Linh Nguyen
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea
| | - Tiep Tien Nguyen
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
| | - Ju-Yeon Kim
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
| | - Jee-Heon Jeong
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Gyeonggi, 16419, Republic of Korea.
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7
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Wan Y, Li S, Xu W, Wang K, Guo W, Yang C, Li X, Zhou J, Wang J. Terminal Chemical Modifications of crRNAs Enable Improvement in the Performance of CRISPR-Cas for Point-of-Care Nucleic Acid Detection. Anal Chem 2024; 96:16346-16354. [PMID: 39348463 DOI: 10.1021/acs.analchem.4c03698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/02/2024]
Abstract
CRISPR-Cas systems, harnessing their precise nucleic acid recognition via CRISPR RNA (crRNA), offer promise for the accurate testing of nucleic acids in the field. However, the inherent susceptibility of crRNA to degradation poses challenges for accurate detection in low-resource settings. Here, we utilized the chemically modified crRNA for the CRISPR-Cas-based assay (CM-CRISPR). We found that the extension and chemical modification to crRNA significantly enhanced the trans-cleavage activity of LbCas12a. The chemically modified crRNA was resistant to degradation, and CM-CRISPR showed superior detection capability in complex environments. CM-CRISPR could be combined with recombinase polymerase amplification (RPA) and applied in a droplet digital platform, enabling attomolar-level sensitivity. We also developed a portable and automated device for a digital CRISPR assay, which is amenable to point-of-care testing (POCT). The extraction-free procedure was integrated with this assay to streamline the workflow, and clinical samples were successfully detected. This work finds a simple and efficient way to improve the performance of CRISPR-Cas and develops a portable platform for POCT, representing a significant advance toward practical applications of CRISPR-based diagnostics.
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Affiliation(s)
- Yunzhu Wan
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Sheng Li
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Wenfei Xu
- Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, Zhejiang 314006, China
| | - Ke Wang
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Wenlong Guo
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
| | - Chongguang Yang
- School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Xuhui Li
- Zhejiang Key Laboratory of Multiomics and Molecular Enzymology, Yangtze Delta Region Institute of Tsinghua University, Zhejiang, Zhejiang 314006, China
| | - Jianhua Zhou
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou 510275, China
| | - Jiasi Wang
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China
- School of Biomedical Engineering, Sun Yat-sen University, Guangzhou 510275, China
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8
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Naghib SM, Ahmadi B, Mikaeeli Kangarshahi B, Mozafari MR. Chitosan-based smart stimuli-responsive nanoparticles for gene delivery and gene therapy: Recent progresses on cancer therapy. Int J Biol Macromol 2024; 278:134542. [PMID: 39137858 DOI: 10.1016/j.ijbiomac.2024.134542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 08/02/2024] [Accepted: 08/04/2024] [Indexed: 08/15/2024]
Abstract
Recent cancer therapy research has found that chitosan (Ch)-based nanoparticles show great potential for targeted gene delivery. Chitosan, a biocompatible and biodegradable polymer, has exceptional properties, making it an ideal carrier for therapeutic genes. These nanoparticles can respond to specific stimuli like pH, temperature, and enzymes, enabling precise delivery and regulated release of genes. In cancer therapy, these nanoparticles have proven effective in delivering genes to tumor cells, slowing tumor growth. Adjusting the nanoparticle's surface, encapsulating protective agents, and using targeting ligands have also improved gene delivery efficiency. Smart nanoparticles based on chitosan have shown promise in improving outcomes by selectively releasing genes in response to tumor conditions, enhancing targeted delivery, and reducing off-target effects. Additionally, targeting ligands on the nanoparticles' surface increases uptake and effectiveness. Although further investigation is needed to optimize the structure and composition of these nanoparticles and assess their long-term safety, these advancements pave the way for innovative gene-focused cancer therapies.
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Affiliation(s)
- Seyed Morteza Naghib
- Nanotechnology Department, School of Advanced Technologies, Iran University of Science and Technology (IUST), Tehran 1684613114, Iran.
| | - Bahar Ahmadi
- Biomaterials and Tissue Engineering Research Group, Interdisciplinary Technologies Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
| | - Babak Mikaeeli Kangarshahi
- State Key Laboratory of Structure Analysis for Industrial Equipment, Department of Engineering Mechanics, Dalian University of Technology, Dalian, China
| | - M R Mozafari
- Australasian Nanoscience and Nanotechnology Initiative (ANNI), Monash University LPO, Clayton, VIC 3168, Australia
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9
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Zai W, Yang M, Jiang K, Guan J, Wang H, Hu K, Huang C, Chen J, Fu W, Zhan C, Yuan Z. Optimized RNA interference therapeutics combined with interleukin-2 mRNA for treating hepatitis B virus infection. Signal Transduct Target Ther 2024; 9:150. [PMID: 38902241 PMCID: PMC11189933 DOI: 10.1038/s41392-024-01871-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 05/06/2024] [Accepted: 05/14/2024] [Indexed: 06/22/2024] Open
Abstract
This study aimed to develop a pan-genotypic and multifunctional small interfering RNA (siRNA) against hepatitis B virus (HBV) with an efficient delivery system for treating chronic hepatitis B (CHB), and explore combined RNA interference (RNAi) and immune modulatory modalities for better viral control. Twenty synthetic siRNAs targeting consensus motifs distributed across the whole HBV genome were designed and evaluated. The lipid nanoparticle (LNP) formulation was optimized by adopting HO-PEG2000-DMG lipid and modifying the molar ratio of traditional polyethylene glycol (PEG) lipid in LNP prescriptions. The efficacy and safety of this formulation in delivering siHBV (tLNP/siHBV) along with the mouse IL-2 (mIL-2) mRNA (tLNP/siHBVIL2) were evaluated in the rAAV-HBV1.3 mouse model. A siRNA combination (terms "siHBV") with a genotypic coverage of 98.55% was selected, chemically modified, and encapsulated within an optimized LNP (tLNP) of high efficacy and security to fabricate a therapeutic formulation for CHB. The results revealed that tLNP/siHBV significantly reduced the expression of viral antigens and DNA (up to 3log10 reduction; vs PBS) in dose- and time-dependent manners at single-dose or multi-dose frequencies, with satisfactory safety profiles. Further studies showed that tLNP/siHBVIL2 enables additive antigenic and immune control of the virus, via introducing potent HBsAg clearance through RNAi and triggering strong HBV-specific CD4+ and CD8+ T cell responses by expressed mIL-2 protein. By adopting tLNP as nucleic acid nanocarriers, the co-delivery of siHBV and mIL-2 mRNA enables synergistic antigenic and immune control of HBV, thus offering a promising translational therapeutic strategy for treating CHB.
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Affiliation(s)
- Wenjing Zai
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Min Yang
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China
- Shanghai Engineering Research Center for Synthetic Immunology, Fudan University, Shanghai, P. R. China
| | - Kuan Jiang
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China
- Eye Institute and Department of Ophthamology, Eye and ENT Hospital, Fudan University, Shanghai, P. R. China
| | - Juan Guan
- Pharmacy Department of Huashan Hospital, Fudan University, Shanghai, P. R. China
| | - Huijing Wang
- Institute of Pediatric Translational Medicine, Shanghai Institute for Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kongying Hu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Chao Huang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China
| | - Wei Fu
- Institute of Pediatric Translational Medicine, Shanghai Institute for Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Changyou Zhan
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, P. R. China.
- Shanghai Engineering Research Center for Synthetic Immunology, Fudan University, Shanghai, P. R. China.
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Research Unit of Cure of Chronic Hepatitis B Virus Infection (CAMS), Shanghai Frontiers Science Center of Pathogenic Microbes and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, P. R. China.
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10
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Sioud M, Juzeniene A, Sæbøe-Larssen S. Exploring the Impact of mRNA Modifications on Translation Efficiency and Immune Tolerance to Self-Antigens. Vaccines (Basel) 2024; 12:624. [PMID: 38932353 PMCID: PMC11209393 DOI: 10.3390/vaccines12060624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/02/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Therapeutic modified mRNAs are being developed for a broad range of human diseases. However, the impact of potential miscoding of modified mRNAs on self-tolerance remains unknown. Additionally, more studies are needed to explore the effects of nucleoside alkylation on translation. While all six tested modifications are tolerated as substrates by T7 RNA polymerase and inhibited mRNA immunogenicity, the translation efficiency varied significantly depending on the type of modification. In contrast to methylation, ethylation at the N1 position of pseudouridine (Ψ) hindered translation, suggesting that the C5-C1' glycosidic bond alone is not a critical element for high translation. Inhibition of mRNA translation was also observed with 5-methoxyuridine modification. However, this inhibition was partially alleviated through the optimization of mRNA coding sequences. BALB/c mice immunized with syngeneic ψ-modified mRNA encoding for Wilms' tumor antigen-1 (WT1) developed a low but significant level of anti-WT1 IgG antibodies compared to those immunized with either unmodified or N1-methyl ψ-modified mRNA. Overall, the data indicate that adding a simple ethyl group (-CH2CH3) at the N1 position of ψ has a major negative effect on translation despite its reduced immunogenicity. Additionally, mRNA containing Ψ may alter translation fidelity at certain codons, which could lead to a breakdown of immune tolerance to self-antigens. This concern should be taken into account during gene replacement therapies, although it could benefit mRNA-based vaccines by generating a diverse repertoire of antigens.
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Affiliation(s)
- Mouldy Sioud
- Department of Cancer Immunology, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379 Oslo, Norway
| | - Asta Juzeniene
- Department of Radiation Biology, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379 Oslo, Norway;
| | - Stein Sæbøe-Larssen
- Department of cellular Therapy, Oslo University Hospital, Radiumhospitalet, Ullernchausseen 70, 0379 Oslo, Norway;
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11
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Androsavich JR. Frameworks for transformational breakthroughs in RNA-based medicines. Nat Rev Drug Discov 2024; 23:421-444. [PMID: 38740953 DOI: 10.1038/s41573-024-00943-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2024] [Indexed: 05/16/2024]
Abstract
RNA has sparked a revolution in modern medicine, with the potential to transform the way we treat diseases. Recent regulatory approvals, hundreds of new clinical trials, the emergence of CRISPR gene editing, and the effectiveness of mRNA vaccines in dramatic response to the COVID-19 pandemic have converged to create tremendous momentum and expectation. However, challenges with this relatively new class of drugs persist and require specialized knowledge and expertise to overcome. This Review explores shared strategies for developing RNA drug platforms, including layering technologies, addressing common biases and identifying gaps in understanding. It discusses the potential of RNA-based therapeutics to transform medicine, as well as the challenges associated with improving applicability, efficacy and safety profiles. Insights gained from RNA modalities such as antisense oligonucleotides (ASOs) and small interfering RNAs are used to identify important next steps for mRNA and gene editing technologies.
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Affiliation(s)
- John R Androsavich
- RNA Accelerator, Pfizer Inc, Cambridge, MA, USA.
- Ginkgo Bioworks, Boston, MA, USA.
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12
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Tang Q, Khvorova A. RNAi-based drug design: considerations and future directions. Nat Rev Drug Discov 2024; 23:341-364. [PMID: 38570694 PMCID: PMC11144061 DOI: 10.1038/s41573-024-00912-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2024] [Indexed: 04/05/2024]
Abstract
More than 25 years after its discovery, the post-transcriptional gene regulation mechanism termed RNAi is now transforming pharmaceutical development, proved by the recent FDA approval of multiple small interfering RNA (siRNA) drugs that target the liver. Synthetic siRNAs that trigger RNAi have the potential to specifically silence virtually any therapeutic target with unprecedented potency and durability. Bringing this innovative class of medicines to patients, however, has been riddled with substantial challenges, with delivery issues at the forefront. Several classes of siRNA drug are under clinical evaluation, but their utility in treating extrahepatic diseases remains limited, demanding continued innovation. In this Review, we discuss principal considerations and future directions in the design of therapeutic siRNAs, with a particular emphasis on chemistry, the application of informatics, delivery strategies and the importance of careful target selection, which together influence therapeutic success.
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Affiliation(s)
- Qi Tang
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA
- Department of Dermatology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Anastasia Khvorova
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA, USA.
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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13
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Teng M, Xia ZJ, Lo N, Daud K, He HH. Assembling the RNA therapeutics toolbox. MEDICAL REVIEW (2021) 2024; 4:110-128. [PMID: 38680684 PMCID: PMC11046573 DOI: 10.1515/mr-2023-0062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/29/2024] [Indexed: 05/01/2024]
Abstract
From the approval of COVID-19 mRNA vaccines to the 2023 Nobel Prize awarded for nucleoside base modifications, RNA therapeutics have entered the spotlight and are transforming drug development. While the term "RNA therapeutics" has been used in various contexts, this review focuses on treatments that utilize RNA as a component or target RNA for therapeutic effects. We summarize the latest advances in RNA-targeting tools and RNA-based technologies, including but not limited to mRNA, antisense oligos, siRNAs, small molecules and RNA editors. We focus on the mechanisms of current FDA-approved therapeutics but also provide a discussion on the upcoming workforces. The clinical utility of RNA-based therapeutics is enabled not only by the advances in RNA technologies but in conjunction with the significant improvements in chemical modifications and delivery platforms, which are also briefly discussed in the review. We summarize the latest RNA therapeutics based on their mechanisms and therapeutic effects, which include expressing proteins for vaccination and protein replacement therapies, degrading deleterious RNA, modulating transcription and translation efficiency, targeting noncoding RNAs, binding and modulating protein activity and editing RNA sequences and modifications. This review emphasizes the concept of an RNA therapeutic toolbox, pinpointing the readers to all the tools available for their desired research and clinical goals. As the field advances, the catalog of RNA therapeutic tools continues to grow, further allowing researchers to combine appropriate RNA technologies with suitable chemical modifications and delivery platforms to develop therapeutics tailored to their specific clinical challenges.
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Affiliation(s)
- Mona Teng
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Ziting Judy Xia
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Nicholas Lo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Kashif Daud
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Housheng Hansen He
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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14
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Nappi F. Non-Coding RNA-Targeted Therapy: A State-of-the-Art Review. Int J Mol Sci 2024; 25:3630. [PMID: 38612441 PMCID: PMC11011542 DOI: 10.3390/ijms25073630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 03/11/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
The use of non-coding RNAs (ncRNAs) as drug targets is being researched due to their discovery and their role in disease. Targeting ncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is an attractive approach for treating various diseases, such as cardiovascular disease and cancer. This seminar discusses the current status of ncRNAs as therapeutic targets in different pathological conditions. Regarding miRNA-based drugs, this approach has made significant progress in preclinical and clinical testing for cardiovascular diseases, where the limitations of conventional pharmacotherapy are evident. The challenges of miRNA-based drugs, including specificity, delivery, and tolerability, will be discussed. New approaches to improve their success will be explored. Furthermore, it extensively discusses the potential development of targeted therapies for cardiovascular disease. Finally, this document reports on the recent advances in identifying and characterizing microRNAs, manipulating them, and translating them into clinical applications. It also addresses the challenges and perspectives towards clinical application.
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Affiliation(s)
- Francesco Nappi
- Department of Cardiac Surgery, Centre Cardiologique du Nord, 93200 Saint-Denis, France
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15
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Pérez-Carrión MD, Posadas I, Ceña V. Nanoparticles and siRNA: A new era in therapeutics? Pharmacol Res 2024; 201:107102. [PMID: 38331236 DOI: 10.1016/j.phrs.2024.107102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 02/10/2024]
Abstract
Since its discovery in 1998, the use of small interfering RNA (siRNA) has been increasing in biomedical studies because of its ability to very selectively inhibit the expression of any target gene. Thus, siRNAs can be used to generate therapeutic compounds for different diseases, including those that are currently 'undruggable'. This has led siRNA-based therapeutic compounds to break into clinical settings, with them holding the promise to potentially revolutionise therapeutic approaches. To date, the United States Food and Drug Administration (FDA) have approved 5 compounds for treating different diseases including hypercholesterolemia, transthyretin-mediated amyloidosis (which leads to polyneuropathy), hepatic porphyria, and hyperoxaluria. This current article presents an overview of the molecular mechanisms involved in the selective pharmacological actions of siRNA-based compounds. It also describes the ongoing clinical trials of siRNA-based therapeutic compounds for hepatic diseases, pulmonary diseases, atherosclerosis, hypertriglyceridemia, transthyretin-mediated amyloidosis, and hyperoxaluria, kidney diseases, and haemophilia, as well as providing a description of FDA-approved siRNA therapies. Because of space constraints and to provide an otherwise comprehensive review, siRNA-based compounds applied to cancer therapies have been excluded. Finally, we discuss how the use of lipid-based nanoparticles to deliver siRNAs holds promise for selectively targeting mRNA-encoding proteins associated with the genesis of different diseases. Thus, siRNAs can help reduce the cellular levels of these proteins, thereby contributing to disease treatment. As consequence, a marked increase in the number of marketed siRNA-based medicines is expected in the next two decades, which will likely open up a new era of therapeutics.
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Affiliation(s)
- María Dolores Pérez-Carrión
- Unidad Asociada CSIC-UCLM Neurodeath. Instituto de Nanociencia Molecular (INAMOL). Universidad de Castilla-La Mancha, Albacete, Spain; CIBER, Instituto de Salud Carlos III, Madrid, Spain
| | - Inmaculada Posadas
- Unidad Asociada CSIC-UCLM Neurodeath. Instituto de Nanociencia Molecular (INAMOL). Universidad de Castilla-La Mancha, Albacete, Spain; CIBER, Instituto de Salud Carlos III, Madrid, Spain
| | - Valentín Ceña
- Unidad Asociada CSIC-UCLM Neurodeath. Instituto de Nanociencia Molecular (INAMOL). Universidad de Castilla-La Mancha, Albacete, Spain; CIBER, Instituto de Salud Carlos III, Madrid, Spain.
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16
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Whalen M, Akula M, McNamee SM, DeAngelis MM, Haider NB. Seeing the Future: A Review of Ocular Therapy. Bioengineering (Basel) 2024; 11:179. [PMID: 38391665 PMCID: PMC10886198 DOI: 10.3390/bioengineering11020179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/03/2024] [Accepted: 02/08/2024] [Indexed: 02/24/2024] Open
Abstract
Ocular diseases present a unique challenge and opportunity for therapeutic development. The eye has distinct advantages as a therapy target given its accessibility, compartmentalization, immune privilege, and size. Various methodologies for therapeutic delivery in ocular diseases are under investigation that impact long-term efficacy, toxicity, invasiveness, and delivery range. While gene, cell, and antibody therapy and nanoparticle delivery directly treat regions that have been damaged by disease, they can be limited in the duration of the therapeutic delivery and have a focal effect. In contrast, contact lenses and ocular implants can more effectively achieve sustained and widespread delivery of therapies; however, they can increase dilution of therapeutics, which may result in reduced effectiveness. Current therapies either offer a sustained release or a broad therapeutic effect, and future directions should aim toward achieving both. This review discusses current ocular therapy delivery systems and their applications, mechanisms for delivering therapeutic products to ocular tissues, advantages and challenges associated with each delivery system, current approved therapies, and clinical trials. Future directions for the improvement in existing ocular therapies include combination therapies, such as combined cell and gene therapies, as well as AI-driven devices, such as cortical implants that directly transmit visual information to the cortex.
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Affiliation(s)
- Maiya Whalen
- Department of Biology, Boston College, Chestnut Hill, MA 02467, USA
| | | | | | - Margaret M DeAngelis
- Department of Ophthalmology, Jacobs School of Medicine & Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
| | - Neena B Haider
- Shifa Precision, Boston, MA 02138, USA
- Department of Cell Biology, Harvard Medical School, Boston, MA 02138, USA
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17
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DeJulius CR, Walton BL, Colazo JM, d'Arcy R, Francini N, Brunger JM, Duvall CL. Engineering approaches for RNA-based and cell-based osteoarthritis therapies. Nat Rev Rheumatol 2024; 20:81-100. [PMID: 38253889 PMCID: PMC11129836 DOI: 10.1038/s41584-023-01067-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2023] [Indexed: 01/24/2024]
Abstract
Osteoarthritis (OA) is a chronic, debilitating disease that substantially impairs the quality of life of affected individuals. The underlying mechanisms of OA are diverse and are becoming increasingly understood at the systemic, tissue, cellular and gene levels. However, the pharmacological therapies available remain limited, owing to drug delivery barriers, and consist mainly of broadly immunosuppressive regimens, such as corticosteroids, that provide only short-term palliative benefits and do not alter disease progression. Engineered RNA-based and cell-based therapies developed with synthetic chemistry and biology tools provide promise for future OA treatments with durable, efficacious mechanisms of action that can specifically target the underlying drivers of pathology. This Review highlights emerging classes of RNA-based technologies that hold potential for OA therapies, including small interfering RNA for gene silencing, microRNA and anti-microRNA for multi-gene regulation, mRNA for gene supplementation, and RNA-guided gene-editing platforms such as CRISPR-Cas9. Various cell-engineering strategies are also examined that potentiate disease-dependent, spatiotemporally regulated production of therapeutic molecules, and a conceptual framework is presented for their application as OA treatments. In summary, this Review highlights modern genetic medicines that have been clinically approved for other diseases, in addition to emerging genome and cellular engineering approaches, with the goal of emphasizing their potential as transformative OA treatments.
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Affiliation(s)
- Carlisle R DeJulius
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Bonnie L Walton
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Juan M Colazo
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Richard d'Arcy
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Nora Francini
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
| | - Jonathan M Brunger
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
| | - Craig L Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
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18
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Yan J, Zhang H, Li G, Su J, Wei Y, Xu C. Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design. Acta Pharm Sin B 2024; 14:579-601. [PMID: 38322344 PMCID: PMC10840434 DOI: 10.1016/j.apsb.2023.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 09/24/2023] [Accepted: 10/08/2023] [Indexed: 02/08/2024] Open
Abstract
Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future.
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Affiliation(s)
- Jing Yan
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Institute of Medicine, Shanghai University, Shanghai 200444, China
| | - Hao Zhang
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Guangfeng Li
- Department of Orthopedics, Shanghai Zhongye Hospital, Shanghai 200941, China
| | - Jiacan Su
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Department of Orthopedics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
- Organoid Research Center, Shanghai University, Shanghai 200444, China
| | - Yan Wei
- Institute of Translational Medicine, Shanghai University, Shanghai 200444, China
- Organoid Research Center, Shanghai University, Shanghai 200444, China
| | - Can Xu
- Department of Gastroenterology, Changhai Hospital, Shanghai 200433, China
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19
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Rana P, Singh C, Kaushik A, Saleem S, Kumar A. Recent advances in stimuli-responsive tailored nanogels for cancer therapy; from bench to personalized treatment. J Mater Chem B 2024; 12:382-412. [PMID: 38095136 DOI: 10.1039/d3tb02650g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2023]
Abstract
To improve the quality of health in a personalized manner, better control over pharmacologically relevant cargo formulation, organ-specific targeted delivery, and on-demand release of therapeutic agents is crucial. Significant work has been put into designing and developing revolutionary nanotherapeutics approaches for the effective monitoring and personalized treatment of disease. Nanogel (NG) has attracted significant interest because of its tremendous potential in cancer therapy and its environmental stimuli responsiveness. NG is considered a next-generation delivery technology due to its benefits like as size tunability, high loading, stimuli responsiveness, prolonged drug release via in situ gelling mechanisms, stability, and its potential to provide personalized therapy from the investigation of human genes and the genes in various types of cancers and its association with a selective anticancer drug. Stimuli-responsive NGs can be used as smart nanomedicines to detect and treat cancer and can be tuned as personalized medicine as well. This comprehensive review article's major objectives include the challenges of NGs' clinical translation for cancer treatment as well as its early preclinical successes and prospects.
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Affiliation(s)
- Prinsy Rana
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
- M. M. College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala-133207, Haryana, India
| | - Charan Singh
- Department of Pharmaceutical Sciences, School of Sciences, Hemvati Nandan Bahuguna Garhwal University (A Central University), Srinagar, Uttarakhand-246174, India
| | - Ajeet Kaushik
- NanoBiotech Lab, Department of Environmental Engineering, Florida Polytechnic University (FPU), Lakeland, FL, 33805-8531, USA
- School of Engineering, University of Petroleum and Energy Studies, Dehradun 248007, India
| | - Shakir Saleem
- Department of Public Health, College of Health Sciences, Saudi Electronic University, P. O. Box 93499, Riyadh 11673, Saudi Arabia
| | - Arun Kumar
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya-824209, India.
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20
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Ma Y, Li S, Lin X, Chen Y. Bioinspired Spatiotemporal Management toward RNA Therapies. ACS NANO 2023; 17:24539-24563. [PMID: 38091941 DOI: 10.1021/acsnano.3c08219] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
Ribonucleic acid (RNA)-based therapies have become an attractive topic in disease intervention, especially with some that have been approved by the FDA such as the mRNA COVID-19 vaccine (Comirnaty, Pfizer-BioNTech, and Spikevax, Moderna) and Patisiran (siRNA-based drug for liver delivery). However, extensive applications are still facing challenges in delivering highly negatively charged RNA to the targeted site. Therapeutic delivery strategies including RNA modifications, RNA conjugates, and RNA polyplexes and delivery platforms such as viral vectors, nanoparticle-based delivery platforms, and hydrogel-based delivery platforms as potential nucleic acid-releasing depots have been developed to enhance their cellular uptake and protect nucleic acid from being degraded by immune systems. Here, we review the growing number of viral vectors, nanoparticles, and hydrogel-based RNA delivery systems; describe RNA loading/release mechanism induced by environmental stimulations including light, heat, pH, or enzyme; discuss their physical or chemical interactions; and summarize the RNA therapeutics release period (temporal) and their target cells/organs (spatial). Finally, we describe current concerns, highlight current challenges and future perspectives of RNA-based delivery systems, and provide some possible research areas that provide opportunities for clinical translation of RNA delivery carriers.
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Affiliation(s)
- Yutian Ma
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - Shiyao Li
- ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Xin Lin
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27705, United States
| | - Yupeng Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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21
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Zhang J, Chen B, Gan C, Sun H, Zhang J, Feng L. A Comprehensive Review of Small Interfering RNAs (siRNAs): Mechanism, Therapeutic Targets, and Delivery Strategies for Cancer Therapy. Int J Nanomedicine 2023; 18:7605-7635. [PMID: 38106451 PMCID: PMC10725753 DOI: 10.2147/ijn.s436038] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023] Open
Abstract
Small interfering RNA (siRNA) delivery by nanocarriers has been identified as a promising strategy in the study and treatment of cancer. Short nucleotide sequences are synthesized exogenously to create siRNA, which triggers RNA interference (RNAi) in cells and silences target gene expression in a sequence-specific way. As a nucleic acid-based medicine that has gained popularity recently, siRNA exhibits novel potential for the treatment of cancer. However, there are still many obstacles to overcome before clinical siRNA delivery devices can be developed. In this review, we discuss prospective targets for siRNA drug design, explain siRNA drug properties and benefits, and give an overview of the current clinical siRNA therapeutics for the treatment of cancer. Additionally, we introduce the siRNA chemical modifications and delivery systems that are clinically sophisticated and classify bioresponsive materials for siRNA release in a methodical manner. This review will serve as a reference for researchers in developing more precise and efficient targeted delivery systems, promoting ongoing advances in clinical applications.
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Affiliation(s)
- Jiaying Zhang
- School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, People’s Republic of China
| | - Bo Chen
- School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, People’s Republic of China
| | - Chunyuan Gan
- School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, People’s Republic of China
| | - Hongyan Sun
- School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, People’s Republic of China
| | - Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Lin Feng
- School of Mechanical Engineering and Automation, Beihang University, Beijing, 100191, People’s Republic of China
- Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, 100191, People’s Republic of China
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22
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Molenda S, Sikorska A, Florczak A, Lorenc P, Dams-Kozlowska H. Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer-Drug Carriers Matter. Cancers (Basel) 2023; 15:5647. [PMID: 38067351 PMCID: PMC10705165 DOI: 10.3390/cancers15235647] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/24/2023] [Accepted: 11/27/2023] [Indexed: 09/08/2024] Open
Abstract
High expression and phosphorylation of signal transducer and transcription activator 3 (STAT3) are correlated with progression and poor prognosis in various types of cancer. The constitutive activation of STAT3 in cancer affects processes such as cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance. The importance of STAT3 in cancer makes it a potential therapeutic target. Various methods of directly and indirectly blocking STAT3 activity at different steps of the STAT3 pathway have been investigated. However, the outcome has been limited, mainly by the number of upstream proteins that can reactivate STAT3 or the relatively low specificity of the inhibitors. A new branch of molecules with significant therapeutic potential has emerged thanks to recent developments in the regulatory function of non-coding nucleic acids. Oligonucleotide-based therapeutics can silence target transcripts or edit genes, leading to the modification of gene expression profiles, causing cell death or restoring cell function. Moreover, they can reach untreatable targets, such as transcription factors. This review briefly describes oligonucleotide-based therapeutics that found application to target STAT3 activity in cancer. Additionally, this review comprehensively summarizes how the inhibition of STAT3 activity by nucleic acid-based therapeutics such as siRNA, shRNA, ASO, and ODN-decoy affected the therapy of different types of cancer in preclinical and clinical studies. Moreover, due to some limitations of oligonucleotide-based therapeutics, the importance of carriers that can deliver nucleic acid molecules to affect the STAT3 in cancer cells and cells of the tumor microenvironment (TME) was pointed out. Combining a high specificity of oligonucleotide-based therapeutics toward their targets and functionalized nanoparticles toward cell type can generate very efficient formulations.
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Affiliation(s)
- Sara Molenda
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Agata Sikorska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Anna Florczak
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Patryk Lorenc
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
| | - Hanna Dams-Kozlowska
- Department of Cancer Immunology, Poznan University of Medical Sciences, 15 Garbary St., 61-866 Poznan, Poland; (S.M.); (A.S.); (A.F.); (P.L.)
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 15 Garbary St., 61-866 Poznan, Poland
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23
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Man HSJ, Moosa VA, Singh A, Wu L, Granton JT, Juvet SC, Hoang CD, de Perrot M. Unlocking the potential of RNA-based therapeutics in the lung: current status and future directions. Front Genet 2023; 14:1281538. [PMID: 38075698 PMCID: PMC10703483 DOI: 10.3389/fgene.2023.1281538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 11/06/2023] [Indexed: 02/12/2024] Open
Abstract
Awareness of RNA-based therapies has increased after the widespread adoption of mRNA vaccines against SARS-CoV-2 during the COVID-19 pandemic. These mRNA vaccines had a significant impact on reducing lung disease and mortality. They highlighted the potential for rapid development of RNA-based therapies and advances in nanoparticle delivery systems. Along with the rapid advancement in RNA biology, including the description of noncoding RNAs as major products of the genome, this success presents an opportunity to highlight the potential of RNA as a therapeutic modality. Here, we review the expanding compendium of RNA-based therapies, their mechanisms of action and examples of application in the lung. The airways provide a convenient conduit for drug delivery to the lungs with decreased systemic exposure. This review will also describe other delivery methods, including local delivery to the pleura and delivery vehicles that can target the lung after systemic administration, each providing access options that are advantageous for a specific application. We present clinical trials of RNA-based therapy in lung disease and potential areas for future directions. This review aims to provide an overview that will bring together researchers and clinicians to advance this burgeoning field.
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Affiliation(s)
- H. S. Jeffrey Man
- Temerty Faculty of Medicine, Institute of Medical Science, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, ON, Canada
- Division of Respirology and Critical Care Medicine, Department of Medicine, University Health Network, Toronto, ON, Canada
| | - Vaneeza A. Moosa
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, ON, Canada
- Division of Thoracic Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - Anand Singh
- Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Licun Wu
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, ON, Canada
- Division of Thoracic Surgery, Toronto General Hospital, Toronto, ON, Canada
| | - John T. Granton
- Division of Respirology and Critical Care Medicine, Department of Medicine, University Health Network, Toronto, ON, Canada
| | - Stephen C. Juvet
- Temerty Faculty of Medicine, Institute of Medical Science, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, ON, Canada
- Division of Respirology and Critical Care Medicine, Department of Medicine, University Health Network, Toronto, ON, Canada
| | - Chuong D. Hoang
- Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Marc de Perrot
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Latner Thoracic Research Laboratories, Toronto General Hospital Research Institute, Toronto, ON, Canada
- Division of Thoracic Surgery, Toronto General Hospital, Toronto, ON, Canada
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24
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Kaushal A. Innate immune regulations and various siRNA modalities. Drug Deliv Transl Res 2023; 13:2704-2718. [PMID: 37219704 PMCID: PMC10204684 DOI: 10.1007/s13346-023-01361-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2023] [Indexed: 05/24/2023]
Abstract
RNAi therapeutics are designed to produce the precise silencing effects against the gene-linked diseases which were known to be untreatable in the past. The highly immunostimulatory nature of siRNA enhances the off-target effects and easily get attacked by nucleases; hence, their modulation is essentially required for accurate alterations to be made in the structures to intensify the pharmacological attributes. The phosphonate modifications act as shield against undue phosphorylation effects, and the molecular changes in ribose sugar lowers the level of immunogenicity and increases the binding efficacy. When bases are substituted with virtual/or pseudo bases, they eventually reduce the off-target effects. These changes modulate the nucleic acid sensors and control the hyper-activation of innate immune response. Various modification designs based on STC (universal pattern), ESC, ESC + (advanced patterns) and disubstrate have been explored to silence the gene expression of various diseases e.g., hepatitis, HIV, influenza, RSV, CNV and acute kidney injury. This review describes the various innovative siRNA therapeutics and their implications on the developed immune regulations to silence the disease effects. siRNA causes the silencing effects through RISC processing. The innate immune signalling is induced by both TLR-dependent and TLR-independent pathways. Modification chemistries are utilized to modulate the immune response.
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Affiliation(s)
- Anju Kaushal
- New Zealand Organization for Quality-Member, Auckland, New Zealand.
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25
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Xie C, Yao R, Xia X. The advances of adjuvants in mRNA vaccines. NPJ Vaccines 2023; 8:162. [PMID: 37884526 PMCID: PMC10603121 DOI: 10.1038/s41541-023-00760-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 10/12/2023] [Indexed: 10/28/2023] Open
Abstract
The remarkable success of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has propelled the rapid development of this vaccination technology in recent years. Over the last three decades, numerous studies have shown the considerable potential of mRNA vaccines that elicit protective immune responses against pathogens or cancers in preclinical studies or clinical trials. These effective mRNA vaccines usually contain specific adjuvants to obtain the desired immune effect. Vaccine adjuvants traditionally are immunopotentiators that bind to pattern recognition receptors (PRRs) of innate immune cells to increase the magnitude or achieve qualitative alteration of immune responses, finally enhancing the efficacy of vaccines. Generally, adjuvants are necessary parts of competent vaccines. According to the existing literature, adjuvants in mRNA vaccines can be broadly classified into three categories: 1) RNA with self-adjuvant characteristics, 2) components of the delivery system, and 3) exogenous immunostimulants. This review summarizes the three types of adjuvants used in mRNA vaccines and provides a comprehensive understanding of molecular mechanisms by which adjuvants exert their functions in mRNA vaccines.
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Affiliation(s)
- Chunyuan Xie
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ruhui Yao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xiaojun Xia
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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Ali Zaidi SS, Fatima F, Ali Zaidi SA, Zhou D, Deng W, Liu S. Engineering siRNA therapeutics: challenges and strategies. J Nanobiotechnology 2023; 21:381. [PMID: 37848888 PMCID: PMC10583313 DOI: 10.1186/s12951-023-02147-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 10/09/2023] [Indexed: 10/19/2023] Open
Abstract
Small interfering RNA (siRNA) is a potential method of gene silencing to target specific genes. Although the U.S. Food and Drug Administration (FDA) has approved multiple siRNA-based therapeutics, many biological barriers limit their use for treating diseases. Such limitations include challenges concerning systemic or local administration, short half-life, rapid clearance rates, nonspecific binding, cell membrane penetration inability, ineffective endosomal escape, pH sensitivity, endonuclease degradation, immunological responses, and intracellular trafficking. To overcome these barriers, various strategies have been developed to stabilize siRNA, ensuring their delivery to the target site. Chemical modifications implemented with nucleotides or the phosphate backbone can reduce off-target binding and immune stimulation. Encapsulation or formulation can protect siRNA from endonuclease degradation and enhance cellular uptake while promoting endosomal escape. Additionally, various techniques such as viral vectors, aptamers, cell-penetrating peptides, liposomes, and polymers have been developed for delivering siRNA, greatly improving their bioavailability and therapeutic potential.
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Affiliation(s)
- Syed Saqib Ali Zaidi
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China
| | - Faria Fatima
- College of Medical Technology, Ziauddin University, Karachi, 74700, Pakistan
| | - Syed Aqib Ali Zaidi
- Shenzhen Key Laboratory of Anti-Aging and Regenerative Medicine, Shenzhen University Medical School, Shenzhen University, Shenzhen, 518060, China
| | - Dezhong Zhou
- School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an, 710049, China.
| | - Wuquan Deng
- Department of Endocrinology and Metabolism, Chongqing Diabetic Foot Medical Research Center, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, 400014, China.
| | - Shuai Liu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
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Kumari A, Kaur A, Aggarwal G. The emerging potential of siRNA nanotherapeutics in treatment of arthritis. Asian J Pharm Sci 2023; 18:100845. [PMID: 37881798 PMCID: PMC10594572 DOI: 10.1016/j.ajps.2023.100845] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 07/14/2023] [Accepted: 08/12/2023] [Indexed: 10/27/2023] Open
Abstract
RNA interference (RNAi) using small interfering RNA (siRNA) has shown potential as a therapeutic option for the treatment of arthritis by silencing specific genes. However, siRNA delivery faces several challenges, including stability, targeting, off-target effects, endosomal escape, immune response activation, intravascular degradation, and renal clearance. A variety of nanotherapeutics like lipidic nanoparticles, liposomes, polymeric nanoparticles, and solid lipid nanoparticles have been developed to improve siRNA cellular uptake, protect it from degradation, and enhance its therapeutic efficacy. Researchers are also investigating chemical modifications and bioconjugation to reduce its immunogenicity. This review discusses the potential of siRNA nanotherapeutics as a therapeutic option for various immune-mediated diseases, including rheumatoid arthritis, osteoarthritis, etc. siRNA nanotherapeutics have shown an upsurge of interest and the future looks promising for such interdisciplinary approach-based modalities that combine the principles of molecular biology, nanotechnology, and formulation sciences.
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Affiliation(s)
- Anjali Kumari
- School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Amanpreet Kaur
- Centre for Advanced Formulation Technology, Delhi Pharmaceutical Sciences and Research, New Delhi 110017, India
- School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
| | - Geeta Aggarwal
- Centre for Advanced Formulation Technology, Delhi Pharmaceutical Sciences and Research, New Delhi 110017, India
- School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India
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Luo T, Huo C, Zhou T, Xie S. Progress on RNA-based therapeutics for genetic diseases. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 52:406-416. [PMID: 37643975 PMCID: PMC10495251 DOI: 10.3724/zdxbyxb-2023-0190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 05/31/2023] [Indexed: 08/01/2023]
Abstract
RNA therapeutics inhibit the expression of specific proteins/RNAs by targeting complementary sequences of corresponding genes or encode proteins for the synthesis desired genes to treat genetic diseases. RNA-based therapeutics are categorized as oligonucleotide drugs (antisense oligonucleotides, small interfering RNA, RNA aptamers), and mRNA drugs. The antisense oligonucleotides and small interfering RNA for treatment of genetic diseases have been approved by the FDA in the United States, while RNA aptamers and mRNA drugs are still in clinical trials. Chemical modifications can be applied to RNA drugs, such as pseudouridine modification of mRNA, to reduce immunogenicity and improve the efficacy. The secure and effective delivery systems such as lipid-based nanoparticles, extracellular vesicles, and virus-like particles are under development to address stability, specificity, and safety issues of RNA drugs. This article provides an overview of the specific molecular mechanisms of eleven RNA drugs currently used for treating genetic diseases, and discusses the research progress of chemical modifications and delivery systems of RNA drugs.
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Affiliation(s)
- Ting Luo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
| | - Chunxiao Huo
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Tianhua Zhou
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou 310058, China.
- The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Center for RNA Medicine, International Institutes of Medicine, Zhejiang University, Jinhua 322000, Zhejiang Province, China.
- Zhejiang University Cancer Center, Hangzhou 310058, China.
| | - Shanshan Xie
- Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
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Khute S, Jangde RK. Optimization of Nasal Liposome Formulation of Venlafaxine Hydrochloride using a Box-Behnken Experimental Design. CURRENT THERAPEUTIC RESEARCH 2023; 99:100714. [PMID: 37727460 PMCID: PMC10506098 DOI: 10.1016/j.curtheres.2023.100714] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Accepted: 08/10/2023] [Indexed: 09/21/2023]
Abstract
Background Intranasal administration is among the most effective alternatives to deliver drugs directly to the brain and prevent first-pass metabolism. Venlafaxine-loaded liposomes are biocompatible carriers that enhance transport qualities over the nasal mucosa. Objective This research aimed to develop, formulate, characterize, and observe the prepared formulation. Methods The formulation was developed using the thin-film hydration technique. The response surface plot interrelationship between three independent variables are lipid, cholesterol and polymer and four dependent variables such as particle size, percentage entrapment efficiency, and percentage drug release were ascertained using the Box-Behnken design. Results The drug-release chitosan-coated liposomes were reported to have a particle size distribution, entanglement efficiency, and 84%, respectively, of 191 ± 34.71 nm, 94 ± 2.71% and 94 ± 2.71%. According to in vitro investigations, liposomes as a delivery system for the nasal route provided a more sustained drug release than the oral dosing form. Conclusions The intranasal administration of venlafaxine liposomal vesicles effectively enhanced the absolute bioavailability, retention time, and brain delivery of venlafaxine.
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Affiliation(s)
- Sulekha Khute
- University Institute of Pharmacy, Pt Ravishankar Shukla University, Chhattisgarh, India
| | - Rajendra K. Jangde
- University Institute of Pharmacy, Pt Ravishankar Shukla University, Chhattisgarh, India
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Chatterjee K, Lakdawala S, Quadir SS, Puri D, Mishra DK, Joshi G, Sharma S, Choudhary D. siRNA-Based Novel Therapeutic Strategies to Improve Effectiveness of Antivirals: An Insight. AAPS PharmSciTech 2023; 24:170. [PMID: 37566146 DOI: 10.1208/s12249-023-02629-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 07/25/2023] [Indexed: 08/12/2023] Open
Abstract
Since the ground-breaking discovery of RNA interference (RNAi), scientists have made significant progress in the field of small interfering RNA (siRNA) treatments. Due to severe barriers to the therapeutic application of siRNA, nanoparticle technologies for siRNA delivery have been designed. For pathological circumstances such as viral infection, toxic RNA abnormalities, malignancies, and hereditary diseases, siRNAs are potential therapeutic agents. However, systemic administration of siRNAs in vivo remains a substantial issue due to a lack of "drug-likeness" (siRNA are relatively larger than drugs and have low hydrophobicity), physiological obstacles, and possible toxicities. This write-up covers important accomplishment in the field of clinical trials and patents specially based of siRNAs using targeting viruses. Furthermore, it offers deep insight of nanoparticle applied for siRNA delivery and strategies to improve the effectiveness of antivirals.
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Affiliation(s)
- Krittika Chatterjee
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS (Deemed to be University), Mumbai, 400056, India
| | - Sagheerah Lakdawala
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS (Deemed to be University), Mumbai, 400056, India
| | - Sheikh Shahnawaz Quadir
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India
| | - Dinesh Puri
- School of Pharmacy, Graphic Era Hill University, Dehradun, Uttarakhand, 248001, India
| | - Dinesh Kumar Mishra
- Department of Pharmacy, Guru Ghasidas Vishwavidyalaya (A Central University), Koni, Bilaspur (C.G.), 495009, India
| | - Garima Joshi
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India
| | - Sanjay Sharma
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS (Deemed to be University), Mumbai, 400056, India.
| | - Deepak Choudhary
- Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, 313001, India.
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Khan S, Rehman U, Parveen N, Kumar S, Baboota S, Ali J. siRNA therapeutics: insights, challenges, remedies and future prospects. Expert Opin Drug Deliv 2023; 20:1167-1187. [PMID: 37642354 DOI: 10.1080/17425247.2023.2251890] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 08/22/2023] [Indexed: 08/31/2023]
Abstract
INTRODUCTION Among conventional and novel therapeutic approaches, the siRNA strategy stands out for treating disease by silencing the gene responsible for the corresponding disorder. Gene silencing is supposedly intended to target any disease-causing gene, and therefore, several attempts and investments were made to exploit siRNA gene therapy and advance it into clinical settings. Despite the remarkable beneficial prospects, the applicability of siRNA therapeutics is very challenging due to various pathophysiological barriers that hamper its target reach, which is the cytosol, and execution of gene silencing action. AREAS COVERED The present review provides insights into the field of siRNA therapeutics, significant in vivo hurdles that mitigate the target accessibility of siRNA, and remedies to overcome these siRNA delivery challenges. Nonetheless, the current review also highlights the on-going clinical trials and the regulatory aspects of siRNA modalities. EXPERT OPINION The siRNAs have the potential to reach previously untreated target sites and silence the concerned gene owing to their modification as polymeric or lipidic nanoparticles, conjugates, and the application of advanced drug delivery strategies. With such mounting research attempts to improve the delivery of siRNA to target tissue, we might shortly witness revolutionary therapeutic outcomes, new approvals, and clinical implications.
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Affiliation(s)
- Saba Khan
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Urushi Rehman
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Neha Parveen
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Shobhit Kumar
- Department of Pharmaceutical Technology, Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh, India
| | - Sanjula Baboota
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
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Mosca N, Russo A, Potenza N. Making Sense of Antisense lncRNAs in Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:8886. [PMID: 37240232 PMCID: PMC10219390 DOI: 10.3390/ijms24108886] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/14/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Transcriptome complexity is emerging as an unprecedented and fascinating domain, especially by high-throughput sequencing technologies that have unveiled a plethora of new non-coding RNA biotypes. This review covers antisense long non-coding RNAs, i.e., lncRNAs transcribed from the opposite strand of other known genes, and their role in hepatocellular carcinoma (HCC). Several sense-antisense transcript pairs have been recently annotated, especially from mammalian genomes, and an understanding of their evolutionary sense and functional role for human health and diseases is only beginning. Antisense lncRNAs dysregulation is significantly involved in hepatocarcinogenesis, where they can act as oncogenes or oncosuppressors, thus playing a key role in tumor onset, progression, and chemoradiotherapy response, as deduced from many studies discussed here. Mechanistically, antisense lncRNAs regulate gene expression by exploiting various molecular mechanisms shared with other ncRNA molecules, and exploit special mechanisms on their corresponding sense gene due to sequence complementarity, thus exerting epigenetic, transcriptional, post-transcriptional, and translational controls. The next challenges will be piecing together the complex RNA regulatory networks driven by antisense lncRNAs and, ultimately, assigning them a function in physiological and pathological contexts, in addition to defining prospective novel therapeutic targets and innovative diagnostic tools.
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Affiliation(s)
| | | | - Nicoletta Potenza
- Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (N.M.); (A.R.)
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Nandi S, Mondal A, Ghosh A, Mukherjee S, Das C. Lnc-ing epigenetic mechanisms with autophagy and cancer drug resistance. Adv Cancer Res 2023; 160:133-203. [PMID: 37704287 DOI: 10.1016/bs.acr.2023.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2023]
Abstract
Long noncoding RNAs (lncRNAs) comprise a diverse class of RNA molecules that regulate various physiological processes and have been reported to be involved in several human pathologies ranging from neurodegenerative disease to cancer. Therapeutic resistance is a major hurdle for cancer treatment. Over the past decade, several studies has emerged on the role of lncRNAs in cancer drug resistance and many trials have been conducted employing them. LncRNAs also regulate different cell death pathways thereby maintaining a fine balance of cell survival and death. Autophagy is a complex cell-killing mechanism that has both cytoprotective and cytotoxic roles. Similarly, autophagy can lead to the induction of both chemosensitization and chemoresistance in cancer cells upon therapeutic intervention. Recently the role of lncRNAs in the regulation of autophagy has also surfaced. Thus, lncRNAs can be used in cancer therapeutics to alleviate the challenges of chemoresistance by targeting the autophagosomal axis. In this chapter, we discuss about the role of lncRNAs in autophagy-mediated cancer drug resistance and its implication in targeted cancer therapy.
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Affiliation(s)
- Sandhik Nandi
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Atanu Mondal
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India
| | - Aritra Ghosh
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Indian Institute of Science Education and Research, Kolkata, India
| | - Shravanti Mukherjee
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India
| | - Chandrima Das
- Biophysics and Structural Genomics Division, Saha Institute of Nuclear Physics, Kolkata, India; Homi Bhabha National Institute, Mumbai, India.
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Shtykalova S, Deviatkin D, Freund S, Egorova A, Kiselev A. Non-Viral Carriers for Nucleic Acids Delivery: Fundamentals and Current Applications. Life (Basel) 2023; 13:903. [PMID: 37109432 PMCID: PMC10142071 DOI: 10.3390/life13040903] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Over the past decades, non-viral DNA and RNA delivery systems have been intensively studied as an alternative to viral vectors. Despite the most significant advantage over viruses, such as the lack of immunogenicity and cytotoxicity, the widespread use of non-viral carriers in clinical practice is still limited due to the insufficient efficacy associated with the difficulties of overcoming extracellular and intracellular barriers. Overcoming barriers by non-viral carriers is facilitated by their chemical structure, surface charge, as well as developed modifications. Currently, there are many different forms of non-viral carriers for various applications. This review aimed to summarize recent developments based on the essential requirements for non-viral carriers for gene therapy.
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Affiliation(s)
- Sofia Shtykalova
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia
- Faculty of Biology, Saint-Petersburg State University, Universitetskaya Embankment 7-9, 199034 Saint-Petersburg, Russia
| | - Dmitriy Deviatkin
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia
- Faculty of Biology, Saint-Petersburg State University, Universitetskaya Embankment 7-9, 199034 Saint-Petersburg, Russia
| | - Svetlana Freund
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia
- Faculty of Biology, Saint-Petersburg State University, Universitetskaya Embankment 7-9, 199034 Saint-Petersburg, Russia
| | - Anna Egorova
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia
| | - Anton Kiselev
- Department of Genomic Medicine, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia
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Foo W, Cseresnyés Z, Rössel C, Teng Y, Ramoji A, Chi M, Hauswald W, Huschke S, Hoeppener S, Popp J, Schacher FH, Sierka M, Figge MT, Press AT, Bauer M. Tuning the corona-core ratio of polyplex micelles for selective oligonucleotide delivery to hepatocytes or hepatic immune cells. Biomaterials 2023; 294:122016. [PMID: 36702000 DOI: 10.1016/j.biomaterials.2023.122016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 01/06/2023] [Accepted: 01/14/2023] [Indexed: 01/22/2023]
Abstract
Targeted delivery of oligonucleotides or small molecular drugs to hepatocytes, the liver's parenchymal cells, is challenging without targeting moiety due to the highly efficient mononuclear phagocyte system (MPS) of the liver. The MPS comprises Kupffer cells and specialized sinusoidal endothelial cells, efficiently clearing nanocarriers regardless of their size and surface properties. Physiologically, this non-parenchymal shield protects hepatocytes; however, these local barriers must be overcome for drug delivery. Nanocarrier structural properties strongly influence tissue penetration, in vivo pharmacokinetics, and biodistribution profile. Here we demonstrate the in vivo biodistribution of polyplex micelles formed by polyion complexation of short interfering (si)RNA with modified poly(ethylene glycol)-block-poly(allyl glycidyl ether) (PEG-b-PAGE) diblock copolymer that carries amino moieties in the side chain. The ratio between PEG corona and siRNA complexed PAGE core of polyplex micelles was chemically varied by altering the degree of polymerization of PAGE. Applying Raman-spectroscopy and dynamic in silico modeling on the polyplex micelles, we determined the corona-core ratio (CCR) and visualized the possible micellar structure with varying CCR. The results for this model system reveal that polyplex micelles with higher CCR, i.e., better PEG coverage, exclusively accumulate and thus allow passive cell-type-specific targeting towards hepatocytes, overcoming the macrophage-rich reticuloendothelial barrier of the liver.
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Affiliation(s)
- WanLing Foo
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Am Klinikum 1, 07747, Jena, Germany
| | - Zoltán Cseresnyés
- Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Research Group Applied Systems Biology, Beutenbergstraße 13, 07745, Jena, Germany
| | - Carsten Rössel
- Friedrich-Schiller-University, Jena Center for Soft Matter, Philosophenweg 7, 07743, Jena, Germany; Friedrich-Schiller-University, Institute of Organic Chemistry and Macromolecular Chemistry (IOMC), Humboldtstraße 10, 07743, Jena, Germany
| | - Yingfeng Teng
- Friedrich-Schiller-University, Computational Materials Science Group, Otto Schott Institute of Materials Research, Faculty of Physics and Astronomy, Löbdergraben 32, 07743, Jena, Germany
| | - Anuradha Ramoji
- Leibniz Institute of Photonic Technology, Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany; Institute of Physical Chemistry (IPC) and Abbe Center of Photonics (ACP), Friedrich-Schiller-University, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Helmholtzweg 4, 07743, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University, Am Klinikum 1, 07747, Jena, Germany
| | - Mingzhe Chi
- Friedrich-Schiller-University, Computational Materials Science Group, Otto Schott Institute of Materials Research, Faculty of Physics and Astronomy, Löbdergraben 32, 07743, Jena, Germany
| | - Walter Hauswald
- Leibniz Institute of Photonic Technology, Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany
| | - Sophie Huschke
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Am Klinikum 1, 07747, Jena, Germany
| | - Stephanie Hoeppener
- Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Research Group Applied Systems Biology, Beutenbergstraße 13, 07745, Jena, Germany; Friedrich-Schiller-University, Institute of Organic Chemistry and Macromolecular Chemistry (IOMC), Humboldtstraße 10, 07743, Jena, Germany
| | - Jürgen Popp
- Leibniz Institute of Photonic Technology, Member of Leibniz Health Technologies, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Albert-Einstein-Straße 9, 07745, Jena, Germany; Institute of Physical Chemistry (IPC) and Abbe Center of Photonics (ACP), Friedrich-Schiller-University, Member of the Leibniz Centre for Photonics in Infection Research (LPI), Helmholtzweg 4, 07743, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University, Am Klinikum 1, 07747, Jena, Germany
| | - Felix H Schacher
- Friedrich-Schiller-University, Jena Center for Soft Matter, Philosophenweg 7, 07743, Jena, Germany; Friedrich-Schiller-University, Institute of Organic Chemistry and Macromolecular Chemistry (IOMC), Humboldtstraße 10, 07743, Jena, Germany
| | - Marek Sierka
- Friedrich-Schiller-University, Jena Center for Soft Matter, Philosophenweg 7, 07743, Jena, Germany; Friedrich-Schiller-University, Computational Materials Science Group, Otto Schott Institute of Materials Research, Faculty of Physics and Astronomy, Löbdergraben 32, 07743, Jena, Germany
| | - Marc Thilo Figge
- Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Research Group Applied Systems Biology, Beutenbergstraße 13, 07745, Jena, Germany; Institute of Microbiology, Faculty of Biological Sciences, Friedrich-Schiller-University Jena, 07743, Jena, Germany; Friedrich-Schiller-University, Jena Center for Soft Matter, Philosophenweg 7, 07743, Jena, Germany
| | - Adrian T Press
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Am Klinikum 1, 07747, Jena, Germany; Friedrich-Schiller-University, Jena Center for Soft Matter, Philosophenweg 7, 07743, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University, Am Klinikum 1, 07747, Jena, Germany; Friedrich-Schiller-University, Faculty of Medicine, Kastanienstraße. 1, 07747, Jena, Germany.
| | - Michael Bauer
- Jena University Hospital, Department of Anesthesiology and Intensive Care Medicine, Am Klinikum 1, 07747, Jena, Germany; Friedrich-Schiller-University, Jena Center for Soft Matter, Philosophenweg 7, 07743, Jena, Germany; Jena University Hospital, Center for Sepsis Control and Care, Friedrich-Schiller-University, Am Klinikum 1, 07747, Jena, Germany.
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Sufian MA, Ilies MA. Lipid-based nucleic acid therapeutics with in vivo efficacy. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1856. [PMID: 36180107 PMCID: PMC10023279 DOI: 10.1002/wnan.1856] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/22/2022] [Accepted: 08/30/2022] [Indexed: 03/09/2023]
Abstract
Synthetic vectors for therapeutic nucleic acid delivery are currently competing significantly with their viral counter parts due to their reduced immunogenicity, large payload capacity, and ease of manufacture under GMP-compliant norms. The approval of Onpattro, a lipid-based siRNA therapeutic, and the proven clinical success of two lipid-based COVID-19 vaccines from Pfizer-BioNTech, and Moderna heralded the specific advantages of lipid-based systems among all other synthetic nucleic acid carriers. Lipid-based systems with diverse payloads-plasmid DNA (pDNA), antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), and messenger RNA (mRNA)-are now becoming a mature technology, with growing impact in the clinic. Research over four decades identified the key factors determining the therapeutic success of these multi-component systems. Here, we discuss the main nucleic acid-based technologies, presenting their mechanism of action, delivery barriers facing them, the structural properties of the payload as well as the component lipids that regulate physicochemical properties, pharmacokinetics and biodistribution, efficacy, and toxicity of the resultant nanoparticles. We further detail on the formulation parameters, evolution of the manufacturing techniques that generate reproducible and scalable outputs, and key manufacturing aspects that enable control over physicochemical properties of the resultant particles. Preclinical applications of some of these formulations that were successfully translated from in vitro studies to animal models are subsequently discussed. Finally, clinical success and failure of these systems starting from 1993 to present are highlighted, in a holistic literature review focused on lipid-based nucleic acid delivery systems. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.
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Affiliation(s)
- Md Abu Sufian
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
| | - Marc A. Ilies
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, School of Pharmacy, Temple University, 3307 North Broad Street, Philadelphia, PA 19140, USA
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37
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Shaharyar MA, Bhowmik R, Al-Abbasi FA, AlGhamdi SA, Alghamdi AM, Sarkar A, Kazmi I, Karmakar S. Vaccine Formulation Strategies and Challenges Involved in RNA Delivery for Modulating Biomarkers of Cardiovascular Diseases: A Race from Laboratory to Market. Vaccines (Basel) 2023; 11:vaccines11020241. [PMID: 36851119 PMCID: PMC9963957 DOI: 10.3390/vaccines11020241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/15/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023] Open
Abstract
It has been demonstrated that noncoding RNAs have significant physiological and pathological roles. Modulation of noncoding RNAs may offer therapeutic approaches as per recent findings. Small RNAs, mostly long noncoding RNAs, siRNA, and microRNAs make up noncoding RNAs. Inhibiting or promoting protein breakdown by binding to 3' untranslated regions of target mRNA, microRNAs post-transcriptionally control the pattern of gene expression. Contrarily, long non-coding RNAs perform a wider range of tasks, including serving as molecular scaffolding, decoys, and epigenetic regulators. This article provides instances of long noncoding RNAs and microRNAs that may be a biomarker of CVD (cardiovascular disease). In this paper we highlight various RNA-based vaccine formulation strategies designed to target these biomarkers-that are either currently in the research pipeline or are in the global pharmaceutical market-along with the physiological hurdles that need to be overcome.
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Affiliation(s)
- Md. Adil Shaharyar
- Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India
| | - Rudranil Bhowmik
- Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India
| | - Fahad A. Al-Abbasi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Shareefa A. AlGhamdi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Amira M. Alghamdi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Arnab Sarkar
- Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: (I.K.); (S.K.); Tel.: +966-543970731 (I.K.); +91-8017136385 (S.K.)
| | - Sanmoy Karmakar
- Bioequivalence Study Centre, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, West Bengal, India
- Correspondence: (I.K.); (S.K.); Tel.: +966-543970731 (I.K.); +91-8017136385 (S.K.)
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38
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Sun D, Lu ZR. Structure and Function of Cationic and Ionizable Lipids for Nucleic Acid Delivery. Pharm Res 2023; 40:27-46. [PMID: 36600047 PMCID: PMC9812548 DOI: 10.1007/s11095-022-03460-2] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 12/08/2022] [Indexed: 01/05/2023]
Abstract
Hereditary genetic diseases, cancer, and infectious diseases are affecting global health and become major health issues, but the treatment development remains challenging. Gene therapies using DNA plasmid, RNAi, miRNA, mRNA, and gene editing hold great promise. Lipid nanoparticle (LNP) delivery technology has been a revolutionary development, which has been granted for clinical applications, including mRNA vaccines against SARS-CoV-2 infections. Due to the success of LNP systems, understanding the structure, formulation, and function relationship of the lipid components in LNP systems is crucial for design more effective LNP. Here, we highlight the key considerations for developing an LNP system. The evolution of structure and function of lipids as well as their LNP formulation from the early-stage simple formulations to multi-components LNP and multifunctional ionizable lipids have been discussed. The flexibility and platform nature of LNP enable efficient intracellular delivery of a variety of therapeutic nucleic acids and provide many novel treatment options for the diseases that are previously untreatable.
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Affiliation(s)
- Da Sun
- Department of Biomedical Engineering, Case Western Reserve University, Wickenden 427, Mail Stop 7207, 10900 Euclid Avenue, Cleveland, OH, 44106, USA
| | - Zheng-Rong Lu
- Department of Biomedical Engineering, Case Western Reserve University, Wickenden 427, Mail Stop 7207, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
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39
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Wu F, Xu X, Li W, Hong Y, Lai H, Zhang J, Wu X, Zhou K, Hu N. Nanoparticle-Delivered Transforming Growth Factor-β1 siRNA Induces PD-1 against Gastric Cancer by Transforming the Phenotype of the Tumor Immune Microenvironment. Pharmaceuticals (Basel) 2022; 15:ph15121487. [PMID: 36558938 PMCID: PMC9787292 DOI: 10.3390/ph15121487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/22/2022] [Accepted: 11/23/2022] [Indexed: 12/02/2022] Open
Abstract
Immune checkpoint blockade (ICB) is currently considered to be an important therapeutic method, which obtained FDA approval for clinical use in gastric cancer in 2017. As a new mechanism, it was found that the effect of αPDL1 could be improved by blocking the TGF-β1 signaling pathway, which converts the tumor immune microenvironment from the "immune-excluded phenotype" to the "immune-inflamed phenotype". Based on this phenomenon, this project was designed to prepare TGF-β1-siRNA-loaded PEG-PCL nanoparticles conjugated to αPDL1 (siTGF-β1-αPDL1-PEG-PCL) since we have linked similar antibodies to PEG-PCL previously. Therefore, MFC tumor-engrafted mice were established to simulate the biological characteristics of converting the phenotype of the immune microenvironment, and to study the anti-tumor effect and possible molecular mechanism. In this study, αPDL1 antibody conjugates markedly increased the cell uptake of NPs. The produced αPDL1-PEG-PCL NPs efficiently reduced the amounts of TGF-β1 mRNA in MFC cells, converting the immune microenvironment of MFC tumors engrafted mice from the "immune-excluded phenotype" to the "immune-inflamed phenotype". PDL1-harboring gastric cancer had increased susceptibility to αPDL1. The value of this drug-controlled release system targeting the tumor microenvironment in immune checkpoint therapy of gastric cancer would provide a scientific basis for clinically applying nucleic acid drugs.
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Affiliation(s)
- Fenglei Wu
- Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
| | - Xiujuan Xu
- Department of Radiation Oncology, Lianyungang Second People’s Hospital (Lianyungang Cancer Hospital), Lianyungang 222023, China
| | - Wei Li
- Center of Research Laboratory, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
| | - Yidong Hong
- Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
| | - Huan Lai
- Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
| | - Jingzhou Zhang
- Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
| | - Xueyu Wu
- Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University (The First People’s Hospital of Lianyungang), Lianyungang 222002, China
| | - Kangjie Zhou
- Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
| | - Nan Hu
- Department of Oncology, The First Affiliated Hospital of Kangda College of Nanjing Medical University (The Affiliated Lianyungang Hospital of Xuzhou Medical University), Xuzhou 221004, China
- Correspondence:
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Hofmeister A, Jahn-Hofmann K, Brunner B, Helms M, Metz-Weidmann C, Krack A, Kurz M, Heubel C, Scheidler S. Small Interfering RNAs Containing Dioxane- and Morpholino-Derived Nucleotide Analogues Show Improved Off-Target Profiles and Chirality-Dependent In Vivo Knock-Down. J Med Chem 2022; 65:13736-13752. [PMID: 36223135 DOI: 10.1021/acs.jmedchem.2c00873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
To expand the applicability of recently developed dioxane- and morpholino-based nucleotide analogues, their seed region destabilizing properties in small interfering RNAs (siRNAs) were investigated in order to improve potential off-target profiles. For this purpose, the corresponding adenosine analogues were synthesized in two diastereomeric series as building blocks for the automated oligonucleotide synthesis. The obtained nucleotide precursors were integrated at position 7 of an siRNA antisense strand, targeting transthyretin messenger RNA. Evaluation of the melting temperatures revealed significant differences in the obtained duplex stabilities between the two diastereomeric series, while the influence of the central scaffold was small. All siRNAs containing these novel nucleotide structures showed improved off-target profiles in vitro compared to their parent sequence with the common 2'-OMe-modified adenosine at the same position. In contrast, in vivo potencies were highly dependent on the chirality within the six-membered nucleotide scaffolds and showed high mRNA downregulations for the (2R,6R)-configured diastereomers.
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Affiliation(s)
- Armin Hofmeister
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
| | | | - Bodo Brunner
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
| | - Mike Helms
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
| | | | - Arne Krack
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
| | - Michael Kurz
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
| | - Christoph Heubel
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
| | - Sabine Scheidler
- Sanofi R&D, Industrial Park Hoechst, Frankfurt am Main 65926, Germany
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41
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Li X, Qi H, Cui W, Wang Z, Fu X, Li T, Ma H, Yang Y, Yu T. Recent advances in targeted delivery of non-coding RNA-based therapeutics for atherosclerosis. Mol Ther 2022; 30:3118-3132. [PMID: 35918894 PMCID: PMC9552813 DOI: 10.1016/j.ymthe.2022.07.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 07/28/2022] [Accepted: 07/30/2022] [Indexed: 10/16/2022] Open
Abstract
Cardiovascular disease (CVD) has overtaken infectious illnesses as the leading cause of mortality and disability worldwide. The pathology that underpins CVD is atherosclerosis, characterized by chronic inflammation caused by the accumulation of plaques in the arteries. As our knowledge about the microenvironment of blood vessel walls deepens, there is an opportunity to fine-tune treatments to target the mechanisms driving atherosclerosis more directly. The application of non-coding RNAs (ncRNAs) as biomarkers or intervention targets is increasing. Although these ncRNAs play an important role in driving atherosclerosis and vascular dysfunction, the cellular and extracellular environments pose a challenge for targeted transmission and therapeutic regulation of ncRNAs. Specificity, delivery, and tolerance have hampered the clinical translation of ncRNA-based therapeutics. Nanomedicine is an emerging field that uses nanotechnology for targeted drug delivery and advanced imaging. Recently, nanoscale carriers have shown promising results and have introduced new possibilities for nucleic acid targeted drug delivery, particularly for atherosclerosis. In this review, we discuss the latest developments in nanoparticles to aid ncRNA-based drug development, particularly miRNA, and we analyze the current challenges in ncRNA targeted delivery. In particular, we highlight the emergence of various kinds of nanotherapeutic approaches based on ncRNAs, which can improve treatment options for atherosclerosis.
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Affiliation(s)
- Xiaoxin Li
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Hongzhao Qi
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Weigang Cui
- Department of Cardiology, People's Hospital of Rizhao, No. 126 Taian Road, Rizhao 276827, People's Republic of China
| | - Zhibin Wang
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266000, China
| | - Xiuxiu Fu
- Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266000, China
| | - Tianxiang Li
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China
| | - Huibo Ma
- Department of Vascular Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao 266021, People's Republic of China.
| | - Tao Yu
- Center for Regenerative Medicine, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, No. 38 Dengzhou Road, Qingdao 266021, People's Republic of China; Department of Cardiac Ultrasound, The Affiliated Hospital of Qingdao University, No.16 Jiangsu Road, Qingdao 266000, China.
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42
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Dong X, Zheng W. Cheminformatics Modeling of Gene Silencing for Both Natural and Chemically Modified siRNAs. Molecules 2022; 27:6412. [PMID: 36234948 PMCID: PMC9570765 DOI: 10.3390/molecules27196412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/23/2022] [Accepted: 09/25/2022] [Indexed: 11/17/2022] Open
Abstract
In designing effective siRNAs for a specific mRNA target, it is critically important to have predictive models for the potency of siRNAs. None of the published methods characterized the chemical structures of individual nucleotides constituting a siRNA molecule; therefore, they cannot predict the potency of gene silencing by chemically modified siRNAs (cm-siRNA). We propose a new approach that can predict the potency of gene silencing by cm-siRNAs, which characterizes each nucleotide (NT) using 12 BCUT cheminformatics descriptors describing its charge distribution, hydrophobic and polar properties. Thus, a 21-NT siRNA molecule is described by 252 descriptors resulting from concatenating all the BCUT values of its composing nucleotides. Partial Least Square is employed to develop statistical models. The Huesken data (2431 natural siRNA molecules) were used to perform model building and evaluation for natural siRNAs. Our results were comparable with or superior to those from Huesken's algorithm. The Bramsen dataset (48 cm-siRNAs) was used to build and test the models for cm-siRNAs. The predictive r2 of the resulting models reached 0.65 (or Pearson r values of 0.82). Thus, this new method can be used to successfully model gene silencing potency by both natural and chemically modified siRNA molecules.
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Affiliation(s)
| | - Weifan Zheng
- BRITE Institute and Department of Pharmaceutical Sciences, College of Health and Sciences (CHAS), North Carolina Central University, Durham, NC 27707, USA
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Amaldoss MJN, Yang JL, Koshy P, Unnikrishnan A, Sorrell CC. Inorganic nanoparticle-based advanced cancer therapies: promising combination strategies. Drug Discov Today 2022; 27:103386. [PMID: 36182068 DOI: 10.1016/j.drudis.2022.103386] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 08/15/2022] [Accepted: 09/24/2022] [Indexed: 11/17/2022]
Abstract
Inorganic nanoparticles for drug delivery in cancer treatment offer many potential advantages because they can maximize therapeutic effect through targeting ligands while minimizing off-target side-effects through drug adsorption and infiltration. Although inorganic nanoparticles were introduced as drug carriers, they have emerged as having the capacity for combined therapeutic capabilities, including anticancer effects through cytotoxicity, suppression of oncogenes and cancer cell signaling pathway inhibition. The most promising advanced strategies for cancer therapy are as synergistic platforms for RNA interference (siRNA, miRNA, shRNA) and as synergistic drug delivery agents for the inhibition of cancer cell signaling pathways. The present work summarizes relevant current work, the promise of which is suggested by a projected compound annual growth rate of ∼20% for drug delivery alone.
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Affiliation(s)
- Maria John Newton Amaldoss
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia; School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia.
| | - Jia-Lin Yang
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Pramod Koshy
- School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Ashwin Unnikrishnan
- Adult Cancer Program, Lowy Cancer Research Centre, Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW 2052, Australia
| | - Charles C Sorrell
- School of Materials Science and Engineering, UNSW Sydney, Sydney, NSW 2052, Australia
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44
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Vaillant A. Oligonucleotide-Based Therapies for Chronic HBV Infection: A Primer on Biochemistry, Mechanisms and Antiviral Effects. Viruses 2022; 14:v14092052. [PMID: 36146858 PMCID: PMC9502277 DOI: 10.3390/v14092052] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/08/2022] [Accepted: 09/08/2022] [Indexed: 11/21/2022] Open
Abstract
Three types of oligonucleotide-based medicines are under clinical development for the treatment of chronic HBV infection. Antisense oligonucleotides (ASOs) and synthetic interfering RNA (siRNA) are designed to degrade HBV mRNA, and nucleic acid polymers (NAPs) stop the assembly and secretion of HBV subviral particles. Extensive clinical development of ASOs and siRNA for a variety of liver diseases has established a solid understanding of their pharmacodynamics, accumulation in different tissue types in the liver, pharmacological effects, off-target effects and how chemical modifications and delivery approaches affect these parameters. These effects are highly conserved for all ASO and siRNA used in human studies to date. The clinical assessment of several ASO and siRNA compounds in chronic HBV infection in recent years is complicated by the different delivery approaches used. Moreover, these assessments have not considered the large clinical database of ASO/siRNA function in other liver diseases and known off target effects in other viral infections. The goal of this review is to summarize the current understanding of ASO/siRNA/NAP pharmacology and integrate these concepts into current clinical results for these compounds in the treatment of chronic HBV infection.
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Affiliation(s)
- Andrew Vaillant
- Replicor Inc., 6100 Royalmount Avenue, Montreal, QC H4P 2R2, Canada
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45
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Godinho BMDC, Knox EG, Hildebrand S, Gilbert JW, Echeverria D, Kennedy Z, Haraszti RA, Ferguson CM, Coles AH, Biscans A, Caiazzi J, Alterman JF, Hassler MR, Khvorova A. PK-modifying anchors significantly alter clearance kinetics, tissue distribution, and efficacy of therapeutics siRNAs. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 29:116-132. [PMID: 35795486 PMCID: PMC9240963 DOI: 10.1016/j.omtn.2022.06.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 06/05/2022] [Indexed: 11/21/2022]
Abstract
Effective systemic delivery of small interfering RNAs (siRNAs) to tissues other than liver remains a challenge. siRNAs are small (∼15 kDa) and therefore rapidly cleared by the kidneys, resulting in limited blood residence times and tissue exposure. Current strategies to improve the unfavorable pharmacokinetic (PK) properties of siRNAs rely on enhancing binding to serum proteins through extensive phosphorothioate modifications or by conjugation of targeting ligands. Here, we describe an alternative strategy for enhancing blood and tissue PK based on dynamic modulation of the overall size of the siRNA. We engineered a high-affinity universal oligonucleotide anchor conjugated to a high-molecular-weight moiety, which binds to the 3' end of the guide strand of an asymmetric siRNA. Data showed a strong correlation between the size of the PK-modifying anchor and clearance kinetics. Large 40-kDa PK-modifying anchors reduced renal clearance by ∼23-fold and improved tissue exposure area under the curve (AUC) by ∼26-fold, resulting in increased extrahepatic tissue retention (∼3- to 5-fold). Furthermore, PK-modifying oligonucleotide anchors allowed for straightforward and versatile modulation of blood residence times and biodistribution of a panel of chemically distinct ligands. The effects were more pronounced for conjugates with low lipophilicity (e.g., N-Acetylgalactosamine [GalNAc]), where significant improvement in uptake by hepatocytes and dose-dependent silencing in the liver was observed.
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Affiliation(s)
- Bruno M D C Godinho
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Emily G Knox
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Samuel Hildebrand
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - James W Gilbert
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Dimas Echeverria
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Zachary Kennedy
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Reka A Haraszti
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Chantal M Ferguson
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Andrew H Coles
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Annabelle Biscans
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Jillian Caiazzi
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Julia F Alterman
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Matthew R Hassler
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
| | - Anastasia Khvorova
- RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA
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Maepa MB, Ely A, Kramvis A, Bloom K, Naidoo K, Simani OE, Maponga TG, Arbuthnot P. Hepatitis B Virus Research in South Africa. Viruses 2022; 14:v14091939. [PMID: 36146747 PMCID: PMC9503375 DOI: 10.3390/v14091939] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/11/2022] [Accepted: 08/26/2022] [Indexed: 11/18/2022] Open
Abstract
Despite being vaccine-preventable, hepatitis B virus (HBV) infection remains the seventh leading cause of mortality in the world. In South Africa (SA), over 1.9 million people are chronically infected with HBV, and 70% of all Black chronic carriers are infected with HBV subgenotype A1. The virus remains a significant burden on public health in SA despite the introduction of an infant immunization program implemented in 1995 and the availability of effective treatment for chronic HBV infection. In addition, the high prevalence of HIV infection amplifies HBV replication, predisposes patients to chronicity, and complicates management of the infection. HBV research has made significant progress leading to better understanding of HBV epidemiology and management challenges in the SA context. This has led to recent revision of the national HBV infection management guidelines. Research on developing new vaccines and therapies is underway and progress has been made with designing potentially curative gene therapies against HBV. This review summarizes research carried out in SA on HBV molecular biology, epidemiology, treatment, and vaccination strategies.
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Affiliation(s)
- Mohube B. Maepa
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, Infectious Diseases and Oncology Research Institute (IDORI), University of the Witwatersrand, Johannesburg 2000, South Africa
- Correspondence:
| | - Abdullah Ely
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, Infectious Diseases and Oncology Research Institute (IDORI), University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Anna Kramvis
- Hepatitis Diversity Research Unit, Department of Internal Medicine, Faculty of Health Sciences, School of Clinical Medicine, University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Kristie Bloom
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, Infectious Diseases and Oncology Research Institute (IDORI), University of the Witwatersrand, Johannesburg 2000, South Africa
| | - Kubendran Naidoo
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, Infectious Diseases and Oncology Research Institute (IDORI), University of the Witwatersrand, Johannesburg 2000, South Africa
- National Health Laboratory Service, Johannesburg 2000, South Africa
| | - Omphile E. Simani
- HIV and Hepatitis Research Unit, Department of Virology, Sefako Makgatho Health Sciences University, Pretoria 0204, South Africa
| | - Tongai G. Maponga
- Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town 7602, South Africa
| | - Patrick Arbuthnot
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, Infectious Diseases and Oncology Research Institute (IDORI), University of the Witwatersrand, Johannesburg 2000, South Africa
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47
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Goyal R, Chopra H, singh I, Dua K, Gautam RK. Insights on prospects of nano-siRNA based approaches in treatment of Cancer. Front Pharmacol 2022; 13:985670. [PMID: 36091772 PMCID: PMC9452808 DOI: 10.3389/fphar.2022.985670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
siRNA interference, commonly referred to as gene silence, is a biological mechanism that inhibits gene expression in disorders such as cancer. It may enhance the precision, efficacy, and stability of medicines, especially genetic therapies to some extent. However, obstacles such as the delivery of oligonucleotide drugs to inaccessible areas of the body and the prevalence of severe side effects must be overcome. To maximize their potential, it is thus essential to optimize their distribution to target locations and limit their toxicity to healthy cells. The action of siRNA may be harnessed to delete a similar segment of mRNA that encodes a protein that causes sickness. The absence of an efficient delivery mechanism that shields siRNA from nuclease degradation, delivers it to cancer cells and releases it into the cytoplasm of specific cancer cells without causing side effects is currently the greatest obstacle to the practical implementation of siRNA therapy. This article focuses on combinations of siRNA with chemotherapeutic drug delivery systems for the treatment of cancer and gives an overview of several nanocarrier formulations in both research and clinical applications.
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Affiliation(s)
- Rajat Goyal
- MM School of Pharmacy, MM University, Sadopur-Ambala, Haryana, India
- MM College of Pharmacy, MM (Deemed to be University), Mullana-Ambala, Haryana, India
| | - Hitesh Chopra
- Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India
| | - Inderbir singh
- Chitkara College of Pharmacy, Chitkara University, Patiala, Punjab, India
| | - Kamal Dua
- Discipline of Pharmacy Graduate School of Health Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine (ARCCIM) University of Technology Sydney, Sydney, NSW, Australia
- *Correspondence: Kamal Dua, ; Rupesh K. Gautam,
| | - Rupesh K. Gautam
- MM School of Pharmacy, MM University, Sadopur-Ambala, Haryana, India
- *Correspondence: Kamal Dua, ; Rupesh K. Gautam,
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Therapeutic Strategies in Huntington’s Disease: From Genetic Defect to Gene Therapy. Biomedicines 2022; 10:biomedicines10081895. [PMID: 36009443 PMCID: PMC9405755 DOI: 10.3390/biomedicines10081895] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/29/2022] [Accepted: 08/03/2022] [Indexed: 12/14/2022] Open
Abstract
Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington’s disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for “gene editing”. Although some issues relating to “off-target” effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington’s disease patients.
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Liu Q, Dai G, Wu Y, Zhang M, Yang M, Wang X, Song M, Li X, Xia R, Wu Z. iRGD-modified exosomes-delivered BCL6 siRNA inhibit the progression of diffuse large B-cell lymphoma. Front Oncol 2022; 12:822805. [PMID: 35982974 PMCID: PMC9378967 DOI: 10.3389/fonc.2022.822805] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 07/01/2022] [Indexed: 11/27/2022] Open
Abstract
Clinical applications of siRNA therapeutics have been limited by the immunogenicity of the siRNA and low efficiency of siRNA delivery to target cells. Recently, evidence have shown that exosomes, endogenous nano-vesicles, can deliver siRNA to the tumor tissues in mice. Here, to reduce immunogenicity, we selected immature dendritic cells (DCs) to produce exosomes. In addition, tumor targeting was achieved by engineering the DCs to express exosomal membrane protein (Lamp2b), fused to av integrin-specific iRGD peptide (CRGDKGPDC). Next, iRGD targeted exosomes (iRGD-Exo) were isolated from the transfected DCs, and then the isolated exosomes were loaded with BCL6 siRNA by electroporation. Our results found that integrin (αvβ3) receptors were highly expressed on OCI-Ly8 cells. In addition, iRGD-Exo showed high targeting ability with avβ3 integrins positive OCI-Ly8 cells. Significantly, iRGD-Exo loaded with BCL6 siRNA suppressed DLBCL cell proliferation in vitro. Furthermore, intravenously injected iRGD-Exo delivered BCL6 siRNA to tumor tissues, resulting in inhibition of tumor growth in DLBCL. Meanwhile, exosomes mediated BCL6 siRNA delivery did not exhibit appreciable toxicity in mice. Collectively, our study demonstrates a therapeutic potential of exosomes as a promising vehicle for RNAi delivery to treat DLBCL.
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Antisense Oligonucleotides and Small Interfering RNA for the Treatment of Dyslipidemias. J Clin Med 2022; 11:jcm11133884. [PMID: 35807171 PMCID: PMC9267663 DOI: 10.3390/jcm11133884] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/21/2022] [Accepted: 07/01/2022] [Indexed: 12/12/2022] Open
Abstract
The burden of atherosclerotic disease worldwide necessitates implementing the treatment of its risk factors. Among them, hypercholesterolemia has a central role. In addition to conventional small organic compounds and the recently introduced monoclonal antibodies, new technologies are arising such as the antisense oligonucleotides and small interfering RNAs (siRNAs) that operate upstream, blocking the mRNA translation of the proteins specifically involved in lipid metabolism. In this review, we briefly explain the mechanisms of action of these molecules and discuss the difficulties related to their in vivo use as therapeutical agents. We go over the oligonucleotides tested in clinical trials that could potentially revolutionize the care of patients by acting on proteins involved in the lipoprotein metabolism and regulation, namely: angiopoietin-like protein 3 (ANGPTL3); lipoprotein a (Lp(a)); apolipoprotein B (Apo B); apolipoprotein C III (Apo C-III); and proprotein convertase subtilisin–kexin type 9 (PCSK9). Finally, the differences between ASOs and siRNAs, their future possible clinical applications, and the role of Inclisiran, a siRNA direct against PCSK9 to reduce LDL-C, were reviewed in detail.
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