TO THE EDITOR
Exosomes, a subclass of small vesicles secreted by eukaryotic cells with diameters typically ranging from 40-100 nm, represent a specific type of extracellular vesicle[1]. The generation process involves endocytosis for the formation of multivesicular bodies, which subsequently undergo fusion with the cell membrane, leading to the extracellular release of intracellular vesicles and their subsequent incorporation into exosomes[2]. Exosomes possess a bilayer phospholipid membrane structure and encapsulate proteins, nucleic acids, lipids, and other bioactive molecules within their interior[2]. Initially believed to serve as a conduit for the disposal of cellular metabolic byproducts, exosomes have been found to play a pivotal role in mediating intercellular communication, orchestrating immune responses, facilitating tumor metastasis, and governing various physiological and pathological processes according to emerging evidence[3].
Exosomes participate in diverse physiological and pathological processes[4]. For instance, within the immune system, exosomes possess the capability to transport antigens and present them to immune cells, thereby eliciting an immunological response or promoting immune tolerance[5]. Exosomes also play part in interneuronal communication within the nervous system, exerting regulatory control over neuronal growth, differentiation, and function[6]. Within the tumor microenvironment, exosomes secreted by neoplastic cells facilitate tumorigenesis, metastasis, and immune evasion through the transfer of microRNAs (miRNAs), proteins, and other bioactive cargo[4].
Hence, exosomes are vital in mediating intercellular communication and exert profound influence on diverse biological processes, encompassing immune response, cellular proliferation, differentiation, and apoptosis. Moreover, the crucial involvement of exosomes in the initiation and progression of various diseases positions them as a significant research target for disease diagnosis and treatment.
EXOSOMES: AN INNOVATIVE PLATFORM FOR DRUG DELIVERY
Owing to their stable presence in bodily fluids, such as blood, urine, and saliva, along with their ability to transport specific protein and nucleic acid molecules, exosomes are regarded as optimal liquid biopsy markers[7]. Early disease diagnosis and prognosis assessment can be accomplished through the analysis of specific molecules within exosomes[8]. Exosomes have garnered significant attention in recent years as cutting-edge drug delivery platforms given their innate biocompatibility, targeted functionality, and minimal immunogenicity[9]. These nanoscale vesicles are naturally secreted by cells and have the capacity to encapsulate a diverse array of biologically active molecules, including proteins, lipids, RNA, and DNA[8,10]. Their distinctive physical and biological characteristics render them optimal vehicles for drug delivery[7]. Exosomes possess an inherent dual-layered membrane structure[11], which enables efficient encapsulation and safeguarding of drug molecules against degradation during transportation[11]. Moreover, exosomes exhibit exceptional biocompatibility and possess the ability to evade immune surveillance, thereby mitigating potential adverse reactions[12]. Exosomes can specifically target cell surface receptors, facilitating precise delivery of therapeutic RNA, proteins, or small molecules to afflicted tissues and thereby enhancing drug efficacy[13]. They can internalize into the cellular interior via endocytosis and subsequently release therapeutic drug molecules, promoting sustained drug delivery and enabling long-term therapeutic efficacy[9]. Therefore, exosomes serve as highly efficient, safe, and precise drug carriers, offering novel insights and methodologies for drug development and clinical application.
At present, the most commonly utilized drug delivery platforms are nanoparticles and liposomes. Nanoparticles show advantages in structural controllability and modifiable drug release rates, but potential risks of toxicity arise[14]. Liposomes have good biocompatibility and lower production cost, which are more suitable for large-scale industrialized production[15]. However, their stability is slightly lower in vivo, and they are easily recognized and cleared by the immune system, which affects their efficacy[16]. By contrast, exosome therapy reduces immune rejection in vivo by virtue of its natural properties, allows for precise targeted delivery in vivo, and crosses some biological barriers (e.g., the blood-brain barrier)[17]. However, it currently faces the challenges of high cost and difficulty in realizing large-scale preparation. With future advances in exosome isolation technology, costs are expected to decline and gradually approach the levels of other established platforms.
In Tang et al's study[18], exosomes were utilized as carriers for gemcitabine (GEM) delivery[18]. This innovative approach not only enhanced the drug's efficacy but also significantly improved its targeting capabilities. By employing electroporation and ultrasound techniques, the researchers successfully encapsulated GEM within exosomes and efficiently delivered it to tumor cells and their microenvironment, thereby greatly augmenting cytotoxicity and apoptosis induction against pancreatic cancer cells[18].
To enhance the targeting and drug-carrying capacity of exosomes, researchers frequently employ modifications and adaptations. For instance, specific targeting ligands can be introduced onto the surface of exosomes to achieve precise recognition of particular cells[19]. Meanwhile, polyethylene glycosylation technology can extend the half-life of exosomes in circulation, enhancing the efficacy of drug delivery[12,20]. The study by Tang et al[18] mentioned the potential enhancement of drug loading efficiency through electroporation and ultrasound methods; however, these techniques may affect the integrity of exosomes, thus influencing their in vivo stability and drug delivery efficacy. Electroporation and ultrasound techniques create temporary or persistent pores in the exosome membrane to allow for effective drug encapsulation and loading[21]. However, such membrane interventions may affect the membrane stability of exosomes, shortening their circulating lifespan and influencing their long-lasting efficacy[22]. Membrane damage induced during electroporation and sonication may also make exosome structures easily recognized by the immune system in vivo, thereby triggering immune clearance and reducing the efficiency of drug delivery[23]. Although electroporation and ultrasound techniques have demonstrated significant advantages in terms of enhanced targeting and efficacy, the effects of these techniques on exosome structural integrity, in vivo stability, and immune response still need to be explored in depth.
In summary, exosomes are emerging as a promising drug delivery platform in modern medical research owing to their distinctive biological properties and broad potential applications, particularly in the fields of cancer and gene therapy.
MESENCHYMAL STEM CELL-DERIVED EXOSOMES IN TUMOR THERAPY
In recent years, mesenchymal stem cell (MSC)-derived exosomes have garnered significant attention in the field of tumor therapy. Tumor cell-derived exosomes have strong homology and can be effectively targeted back to tumor cells or the tumor microenvironment, but safety still needs to be evaluated[24]. Immunocyte exosomes are immune specific in targeting foci of infection or tumors; however, the manufacturing process is complex, production is limited, and an immune system over-reaction may be triggered[3]. Neural cell exosomes show unique advantages in crossing the blood-brain barrier, but their stability under in vitro culture conditions is relatively low[25]. Meanwhile, erythrocyte exosomes are suitable for long-acting delivery but are limited in the types of drugs they can be loaded with and the targets they can target[26]. MSC-derived exosomes possess distinct advantages for tumor treatment. Compared with exosomes derived from alternative sources, MSC exosomes exhibit reduced immunogenicity and demonstrate remarkable efficacy in immune response suppression, graft rejection reduction, and facilitation of tissue repair processes[27]. Moreover, they promote cellular proliferation while inhibiting apoptosis through the delivery of miRNAs, proteins, and other bioactive molecules[28]. MSCs can be derived from diverse sources, including bone marrow and adipose tissue, exhibit facile scalability, and possess a favorable safety profile, rendering them highly promising candidates for tumor therapy[29].
MSC-derived exosomes have been utilized as carriers for anticancer agents in the context of cancer therapy[30]. Targeted treatment of cancer cells can be achieved by encapsulating chemotherapeutic drugs within exosomes[28]. For instance, through engineering modifications, MSC-derived exosomes can be effectively loaded with the anticancer drug Adriamycin[31-33]. The utilization of exosomes as carriers for anticancer drugs has demonstrated the ability to enhance drug concentration at tumor sites while minimizing toxicity toward normal cells[13,33]. Targeted delivery of drugs can be enhanced by modifying specific peptides or antibodies on the surface of exosomes, thus significantly improving antitumor effects while minimizing drug-related side effects[29,34]. In the study of colorectal cancer, the use of MSC exosomes loaded with 5-fluorouracil (5-FU) for delivery not only enhanced the targeting of 5-FU but also significantly increased the antitumor activity of the drug[35]. Targeted delivery of paclitaxel to lung cancer cells using engineered exosomes can effectively enhance drug concentration and reduce side effects[36]. In particular, through surface modification of lung-targeting peptides, exosome-carried paclitaxel can specifically accumulate in lung tumor tissues, significantly reducing the toxicity to normal lung tissues[36]. For malignant gliomas, a difficult-to-treat brain tumor, MSC-derived exosomes exhibit natural blood-brain barrier penetration ability[37]. In related studies, MSC exosomes carrying temozolomide can be successfully delivered to glioma cells, effectively penetrating the blood-brain barrier and realizing precise treatment of brain tumors[37,38].
MSC-derived exosomes possess immunomodulatory molecules that augment antitumor immune responses. For instance, these exosomes can effectively transport antigens essential for antigen-presenting cells, thereby facilitating the recognition and elimination of cancerous cells by the immune system[20]. Furthermore, MSC exosomes have been utilized as carriers for gene therapies, including small interfering RNAs (siRNAs), miRNAs, and messenger RNAs, to effectively modulate or silence specific gene expression in cancer cells[39]. Notably, studies have demonstrated that targeted delivery of siRNAs via MSC exosomes can significantly downregulate the expression of oncogenic genes, impede tumor growth, and attenuate the metastatic potential of cancer cells by evading immune surveillance[40,41].
Clinical studies of exosome therapy are currently small in number, focusing on chronic diseases, infectious diseases, and oncology. Phase II/III trials based on exosomes derived from umbilical cord MSCs in patients with chronic kidney disease have shown no significant adverse effects reported by patients, and improvements in renal function and inflammatory markers have been noted with the development of technology and the expansion of trial sizes[42]. In the treatment of coronavirus disease 2019, exosomal trials derived from bone marrow MSCs have initially demonstrated a positive effect in terms of safety and partial efficacy[43]. Meanwhile, tumor-specific studies have exhibited a favorable safety profile of ascites-derived exosomes in combination with Granulocyte-Macrophage Colony Stimulating factor in colorectal cancer patients[44]. Overall, although exosome therapies show promising potential, the current number of clinical trials is still in the early exploratory stage, and the sample size is limited. As technology develops and trial sizes expand, they are expected to become a new treatment option in the future.
This study investigates the findings of research on the isolation of exosomes from human bone marrow MSCs and their potential application in GEM delivery for pancreatic cancer therapy. MSC-derived exosomes possess a distinctive ability to recognize and target inflammatory sites, as well as tumor microenvironments. Research has significantly enhanced cytotoxicity and promoted apoptosis in pancreatic cancer cells by loading GEM into MSC-derived exosomes using electroporation and ultrasound techniques, offering novel insights for overcoming drug resistance in pancreatic cancer.
In conclusion, the investigation of therapeutics utilizing MSC-derived exosome-bound drugs exhibits a promising and extensive scope for tumor therapy. With further elucidation of their mechanism of action and optimization strategies, MSC-derived exosomes are anticipated to assume a pivotal role in clinical applications.
Tang et al's study[18] investigated the potential of human bone marrow MSC-derived exosomes as a drug delivery platform for GEM in pancreatic cancer cells. The experimental findings demonstrated that GEM-loaded exosomes (Exo-GEM) exhibited enhanced efficacy in inducing apoptosis compared with free GEM, highlighting their promising role as an innovative drug delivery system and offering a novel therapeutic strategy for pancreatic cancer chemotherapy.
However, the aforementioned study has certain limitations. The efficacy of Exo-GEM has only been verified through in vitro experiments, lacking in vivo experimental data to substantiate its feasibility and safety for clinical application. Although the electroporation and ultrasound methods mentioned in the study have enhanced drug loading efficiency, they may potentially compromise the integrity of exosomes, affecting their stability and effectiveness as drug delivery vehicles in vivo. Furthermore, while the use of exosomes as a drug delivery platform is an innovative aspect of this study, more experimental evidence is required to support its specific effect on drug-resistant cancer cells. Therefore, future studies should focus on optimizing exosome isolation and drug loading techniques and validating the efficacy and safety of Exo-GEM using animal models.
Exosomes possess a promising application potential as a drug delivery platform, offering improvements in drug targeting and reduced side effects. Moreover, they may play a crucial role in overcoming resistance to conventional chemotherapeutic drugs. With further research advancements, exosome technology is anticipated to emerge as an innovative and effective drug delivery system within the field of cancer therapy, providing patients with more precise and personalized treatment strategies. However, some challenges occur in practical application. First, the natural production of exosomes is low, and the cost and yield are high and hardly meet the clinical demand. Second, the safety of exosomes should be considered in advancing their clinical application. The composition and properties of exosomes, as a biogenic nanocarrier, are susceptible to influence, and the quality of exosomes is difficult to be completely consistent between different production batches, which in turn affects the stability of therapeutic effects. Third, exosomes are naturally present in the body; however, exosomes from different cellular sources may carry heterogeneity, and some components may trigger host immune responses. Fourth, exosomes face complex regulatory challenges in clinical translation. Because of their characteristics as drugs, cell therapies, and gene therapies, regulatory agencies in different countries and regions often lack uniform standards for evaluating their safety and efficacy, resulting in a complex and lengthy approval process. Future investigations will focus on addressing these issues by developing standardized methods for exosome preparation while exploring their application across different cancer types. Furthermore, efforts will be made to establish regulated and controllable therapeutic approaches involving exosomes to enhance their prospects for clinical treatment.
