The formidable contractile tension exerted by cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) tissue is crucial for maintaining high tissue solid stress (TSS), which impedes the delivery and penetration of chemotherapeutic drugs. To address this obstacle, we constructed a pH-responsive nanotension relief agent (FS@MMS), in which fasudil (FS) was ingeniously conjugated to mesoporous silica encapsulated with magnetic iron oxide (MMS). The nanotension relief agent was demonstrated to inhibit the synthesis of phosphorylated myosin light chain by blocking the Rho/Rho-associated serine/threonine kinase (ROCK) pathway, triggering the swift transformation of high-tension CAFs into low-tension CAFs in PDAC tissue, which relieves TSS and enhances drug penetration in Panc02/NIH-3T3 multicellular tumor spheroids. When the nanotension relief agent was further loaded with the chemotherapeutic drug gemcitabine (GEM), as FS@MMS-GEM, the enhanced permeation of GEM progressively killed tumor cells and amplified their TSS-relief properties, thereby maximizing the anticancer efficacy of chemotherapeutic agents in Panc02/NIH-3T3 coplanted model mice. The magnetic resonance imaging results revealed that the synergistic effect substantially improved drug delivery and penetration efficiency. The developed approach holds great potential for improving chemotherapy efficacy in PDAC and provides a novel therapeutic approach for the treatment of related stroma-rich tumors.

Individual theranostics with an integrated multifunction holds considerable promise for clinical application compared with multicomponent regimes. Mn3O4 nanoparticles with an ultrasmall size (4 nm) and mass production capability were developed with dual function of integrated tumor magnetic resonance imaging (MRI) and therapy. The high valence state of Mn3O4 nanocrystals enables a sensitive reaction with the glutathione (GSH) molecule and favorable decomposition ability, which further induces a unique, favorable, variable T 1 turn-off and T 2 turn-on MRI property. In addition, ultrasmall Mn3O4 nanoparticles reacted with high-level GSH in the tumor microenvironment induces responsive and enhanced variable T 1- and T 2-MRI imaging capability for accurate cancer diagnosis. Moreover, the synthesized ultrasmall Mn3O4 nanoparticles exhibit considerable ferroptosis effect towards tumor cells and excellent in vivo biocompatibility, thus indicating promising effective cancer treatment application. The developed ultrasmall Mn3O4 nanoparticles with integrated dual functions of GSH-responsive variable T 1 and T 2 MRI imaging effects and ferroptosis capability show promising potential as a candidate for tumor theranostics in clinical applications.

Iron oxide nanoparticles (MNPs) demonstrate notable benefits in magnetic induction, attributed to their distinctive physical and chemical attributes. Emerging cancer treatment utilizing magnetic fields have also gathered increasing attention in the biomedical field. However, the defects of difficult dispersion and poor biocompatibility of MNPs seriously hinder their application. In order to overcome its inherent defects and maximize the therapeutic potential of MNPs, various functionalized MNPs have been developed, and numerous combined treatment methods based on MNPs have been widely studied. In this review, we compare and analyze the common nanoparticles based on MNPs with different sizes, shapes, and functional modifications. Additionally, we introduced the therapeutic mechanisms of the strategies, such as magnetically controlled targeting, magnetic hyperthermia, and magneto-mechanical effect, which based on the unique magnetic induction capabilities of MNPs. Finally, main challenges of MNPs as smart nanomaterials were also discussed. This review seeks to offer a thorough overview of MNPs in biomedicine and a new sight for their application in tumor treatment.

Due to the uncertain differentiation of neural stem cells (NSCs), replenishing lost neurons by endogenous neural differentiation to repair spinal cord injury (SCI) remains challenging. The electrical stimulation-induced drug release is a promising approach for the localized and controlled release of drugs to regulate the differentiation of NSCs into neurons. Here, we developed Zn-PDA@BT nanoparticles acted as Trojan Horse to enter cells through endocytosis for Zn2+-controlled release therapy by the potentials generated by the piezoelectric effect. Due to the presence of polydopamine (PDA), under ultrasound stimulation, the electrical signal derived from the piezoelectric effect of barium titanate nanoparticles can be attracted to the surface of Trojan Horse nanoparticles to facilitate the controlled release of Zn2+. And Zn2+ bonded with PDA can increase the intracellular Zn2+ concentration within mouse-derived NSCs (mNSCs) to regulate the differentiation of mNSCs, which could enhance excitatory neuronal differentiation and inhibit astrocyte differentiation of mNSCs by activating the TGF-β and p53 pathways. More importantly, this Trojan Horse therapy allowed mNSCs to differentiate into mature neurons in 5 days, while the natural differentiation process took 10 days. Moreover, the transplantation of mNSC-ingested Zn-PDA@BT nanoparticles effectively replenished lost neurons at the damaged site and promoted function recovery after SCI in vivo, demonstrating the great potential of electrical stimulation-induced Zn2+ release for SCI repair.

Cancer research has become increasingly complex over the past few decades as knowledge of the heterogeneity of cancer cells, their proliferative ability, and their tumor microenvironments has become available. Although conventional therapies remain the most compelling option for cancer treatment to date, immunotherapy is a promising way to harness natural immune defenses to target and kill cancer cells. Cell-mediated drug delivery systems (CDDSs) have been an active line of research for enhancing the therapeutic efficacy and specificity of cancer immunotherapy. These systems can be tailored to different types of immune cells, allowing immune evasion and accumulation in the tumor microenvironment. By enabling the targeted delivery of therapeutic agents such as immune stimulants, cytokines, antibodies, and antigens, CDDSs have improved the survival of some patients with cancer. This review summarizes the research status of CDDSs, with a focus on their underlying mechanisms of action, biology, and clinical applications. We also discuss opportunities and challenges for implementation of CDDSs into mainstream cancer immunotherapy.

Adoptive cellular immunotherapy as a promising and alternative cancer therapy platform is critical for future clinical applications. Natural killer (NK) cells have attracted attention as an important type of innate immune regulatory cells that can rapidly kill multiple adjacent cancer cells. However, these cells are significantly less effective in treating solid tumors than in treating hematological tumors. Herein, we report the synthesis of a Fe3O4-PEG-CD56/Avastin@Ce6 nanoprobe labeled with NK-92 cells that can be used for adoptive cellular immunotherapy, photodynamic therapy and dual-modality imaging-based in vivo fate tracking. The labeled NK-92 cells specifically target the tumor cells, which increases the amount of cancer cell apoptosis in vitro. Furthermore, the in vivo results indicate that the labeled NK-92 cells can be used for tumor magnetic resonance imaging and fluorescence imaging, adoptive cellular immunotherapy, and photodynamic therapy after tail vein injection. These data show that the developed multifunctional nanostructure is a promising platform for efficient innate immunotherapy, photodynamic treatment and noninvasive therapeutic evaluation of breast cancer.

Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective treatment, which endow the providential treatment and avoid the repeated medication with side effects. However, it is difficult to achieve the integrated strategy of MRI and therapeutic drug due to complicated synthesis route, low efficiency and potential biosafety issues. In this study, novel self-assembled ultrasmall Fe3O4 nanoclusters were developed for tumor-targeted dual-mode T1/T2-weighted magnetic resonance imaging (MRI) guided synergetic chemodynamic therapy (CDT) and chemotherapy. The self-assembled ultrasmall Fe3O4 nanoclusters synthesized by facilely modifying ultrasmall Fe3O4 nanoparticles with 2,3-dimercaptosuccinic acid (DMSA) molecule possess long-term stability and mass production ability. The proposed ultrasmall Fe3O4 nanoclusters shows excellent dual-mode T1 and T2 MRI capacities as well as favorable CDT ability due to the appropriate size effect and the abundant Fe ion on the surface of ultrasmall Fe3O4 nanoclusters. After conjugation with the tumor targeting ligand Arg-Gly-Asp (RGD) and chemotherapy drug doxorubicin (Dox), the functionalized Fe3O4 nanoclusters achieve enhanced tumor accumulation and retention effects and synergetic CDT and chemotherapy function, which serve as a powerful integrated theranostic platform for cancer treatment.

Adoptively transferred cells usually suffer from exhaustion, limited expansion, and poor infiltration, partially attributing to the complicated immunosuppressive microenvironment of solid tumors. Therefore, it is necessary to explore more effective strategies to improve the poor tumor microenvironment (TME) to efficaciously deliver and support extrinsic effector cells in vivo. Herein, an intelligent biodegradable hollow manganese dioxide nanoparticle (MnOX) that possesses peroxidase activity to catalyze excess H2O2 in the TME to produce oxygen and relieve the hypoxia of solid tumors is developed. MnOX nanoenzymes modified with CD56 antibody could specifically bind CAR-NK (chimeric antigen receptor modified natural killer) cells. It is demonstrated that CAR-NK cells incorporated with MnOX nanoenzymes effectively infiltrate into tumor tissues with an improved TME, which results in superior antitumor activity in solid tumor-bearing mice. The antibody connection between MnOX nanoenzymes and CAR-NK endows the lowest efficient dosage of MnOX. This study features a smart synergistic immunotherapy approach for solid tumors using MnOX nanoenzyme-armed CAR-NK cells, which would provide a valuable tool for immunocyte therapy in solid tumors.

Cancer immunotherapy can significantly prevent tumor growth and metastasis by activating the autoimmune system without destroying normal cells. Although cancer immunotherapy has made some achievements in clinical cancer treatment, it is still restricted by systemic immunotoxicity, immune cell dysfunction, cancer heterogeneity, and the immunosuppressive tumor microenvironment (ITME). Biomimetic cell-derived nanoparticles are attracting considerable interest due to their better biocompatibility and lower immunogenicity. Moreover, biomimetic cell-derived nanoparticles can achieve different preferred biological effects due to their inherent abundant source cell-relevant functions. This review summarizes the latest developments in biomimetic cell-derived nanoparticles for cancer immunotherapy, discusses the applications of each biomimetic system in cancer immunotherapy, and analyzes the challenges for clinical transformation.

NK cell immunotherapy is a promising antitumor therapeutic modality after the development of T cell immunotherapy. Structural modification of NK cells with biomaterials may provide a precise, efficient, and low-cost strategy to enhance NK cell immunotherapy. The biomaterial modification of NK cells can be divided into two strategies: surface engineering with biomaterials and intracellular modification. The surface engineering strategies include hydrophobic interaction of lipids, receptor-ligand interaction between membrane proteins, covalent binding to amino acid residues, click reaction and electrostatic interaction. The intracellular modification strategies are based on manipulation by nanotechnology using membranous materials from various sources of NK cells (such as exosome, vesicle and cytomembranes). Finally, the biomaterials-based strategies regulate the recruitment, recognition and cytotoxicity of NK cells in the solid tumor site in situ to boost the activity of NK cells in the tumor. This article reviews the recent research progress in enhancing NK cell therapy based on biomaterial modification, to provide a reference for further researches on engineering NK cell therapy with biomaterials.

Nanomedicine offers considerable opportunities to improve drugability and reduce toxicity for tumour therapy. However, the application of nanomedicine has achieved little success in clinical trials due to multiple physiological barriers to drug delivery. Circulating cells are expected to improve the physical distribution of drugs and enhance the therapeutic effect by overcoming various biological barriers in collaboration with nano-drug delivery systems owing to excellent biocompatibility, low immunogenicity and a long-circulation time and strong binding specificity. Nonetheless, we have noticed some limitations in implementing tthe strategy. In this article, we intend to introduce the latest progress in research and application of circulating cell-mediated nano-drug delivery systems, describe the main cell-related drug delivery modes, sum up the relevant points of the transport systems in the process of loading, transport and release, and lastly discuss the advantages, challenges and future development trends in cell-mediated nano-drug delivery.

Cancer immunotherapy is a therapeutic strategy to inhibit tumor growth and metastasis by intervening in the immune response process. Strategies applied to cancer immunotherapy mainly include blocking immune checkpoints, adoptive transfer of engineered immune cells, cytokine therapy, cancer vaccines, and oncolytic virus infection. However, many factors, such as off-target side effects, immunosuppressive cell infiltration and/or upregulation of immune checkpoint expression, cancer cell heterogeneity, and lack of antigen presentation, affect the therapeutic effect of immunotherapy on cancer. To improve the efficacy of targeted immunotherapy and reduce off-target effects, over the past two decades, nanoparticle delivery platforms have been increasingly used in tumor immunotherapy. However, nanoparticles are still subject to biological barriers and biodistribution challenges, which limit their overall clinical potential. This has prompted a series of engineered nanoparticles to overcome specific obstacles and transfer the accumulation of payloads to tumor-infiltrating immune cells. In recent years, new techniques and chemical methods have been employed to modify or functionalize the surfaces of nanoparticles. This review discusses the recent progress of surface-engineered nanoparticles in inducing tumor immune responses and immunotherapy, as well as future directions for the development of next-generation nanomedicines.

Living cells have become ideal therapeutic agents for cancer treatment owing to their innate activities, such as efficient tumor targeting and delivery, easy engineering, immunomodulatory properties, and fewer adverse effects. However, cell agents are often fragile to rigorous tumor microenvironment (TME) and limited by inadequate therapeutic responses, leading to unwanted treatment efficacy. Cell nanomodification, particularly the cell surface-nanoengineering has emerged as reliable and efficient strategy that not only combines cell activity properties with nanomaterials but also endows them with extra novel functions, enabling to achieve remarkable treatment results. In this review, we systematically introduce two major strategies have been adopted to develop cell surface engineering with nanomaterials, mainly including living cell nano-backpacks and cell membrane-mimicking nanoparticles (NPs). Based on various functional NPs and cell types, we focus on reviewing the cell-surface nanoengineering for targeted drug delivery, immune microenvironment regulation, and precisely antitumor therapy. The advances and challenges of cell surface-nanoengineered antitumor agents for cancer therapy applications are further discussed in future clinical practice. This review provides an overview of the advances in cell surface-engineering for targeting immunoregulation and treatment and could contribute to the future of advanced cell-based antitumor therapeutic applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Cells at the Nanoscale.

Neural cell adhesion molecule, an integrated molecule of immunoglobulin protein superfamily involved in cell-cell adhesion, undergoes various structural modifications through numerous temporal-spatial regulations that generously alter their expressions on cell surfaces. These varied expression patterns are mostly envisioned in the morphogenesis and innervations of different human organs and systems. The considerable role of NCAM in neurite growth, brain development and etc. and its altered expression of NCAM in proliferating tumour cells and metastasis of various human melanomas clearly substantiate its appropriateness as a cell surface marker for diagnosis and potential target for several therapeutic moieties. This characteristic behaviour of NCAM is confined to its novel biochemistry, structural properties, signalling interactions and polysialylation. In particular, the characteristic expressions of NCAM are mainly attributed by its polysialylation, a post-translational modification that attaches polysialyl groups to the NCAM. The altered expression of NCAM on cell surface develops curiosity amidst pharmaceutical scientists, which drives them to understand its role of such expressions in various human melanomas and to elucidate the promising therapeutic strategies that are currently available to target NCAM appositely. Therefore, this review article is articulated with an insight on the altered expressions of NCAM, the clinical significances and the consequences of such atypical expression patterns in various human organs and systems.

Targeted delivery of pharmaceuticals is promising for efficient disease treatment and reduction in adverse effects. Nano or microstructured magnetic materials with strong magnetic momentum can be noninvasively controlled via magnetic forces within living beings. These magnetic carriers open perspectives in controlling the delivery of different types of bioagents in humans, including small molecules, nucleic acids, and cells. In the present review, we describe different types of magnetic carriers that can serve as drug delivery platforms, and we show different ways to apply them to magnetic targeted delivery of bioagents. We discuss the magnetic guidance of nano/microsystems or labeled cells upon injection into the systemic circulation or in the tissue; we then highlight emergent applications in tissue engineering, and finally, we show how magnetic targeting can integrate with imaging technologies that serve to assist drug delivery.