Biomaterials Science2022ReviewNon-viral Gene Delivery
Sydney R. Shannon, Elena Ben-Akiva, Jordan J. Green
Gene therapies are transforming treatment for many diseases, but clinical efficacy and safety depend on both the delivery material and the cargo. Non-viral delivery to immune cells remains especially challenging, and no clinical translation breakthrough has yet been achieved for non-viral gene editing. This mini-review addresses that gap by surveying biomaterial-based delivery to immune cells, CRISPR/Cas9 cargo options, and how the two fields can be integrated for cancer immunotherapy. --- - PBAE nanoparticles with anti-CD3ε Fab2, MTAS, and NLS delivered DNA encoding leukemia-specific CARs to T cells at 34% efficiency *in vivo*, programming functional antigen recognition and anti-tumor effects. - PBAE mRNA CAR nanoparticles (anti-CD8, PGA-coated) transiently transfected T cells at 10% efficiency *in vivo*. - CART polymers: ~80% mRNA transfection in Jurkat T cells *in vitro*, but only ~1.5% *in vivo*; mixed hydrophobic blocks outperforme
Read the article →Acta Pharmaceutica Sinica B2022ReviewNon-viral Gene Delivery
Yingping Zeng, Sufen Li, Shufen Zhang, Li Wang, Hong Yuan, Fuqiang Hu
Cancer immunotherapy is limited by tumor heterogeneity, immune cell disability, immunosuppressive tumor microenvironment (TME), and systemic immune toxicity. Cell membrane-coated nanoparticles (CMCNs) offer a biomimetic delivery strategy that inherits source-cell functions—immune evasion, tumor targeting, and biological compatibility—to precisely deliver immunotherapeutic drugs and enhance anti-cancer immunity. --- - Cancer vaccine response rates: clinical patient response to cancer vaccines remains relatively low at 11–50%; ICB inhibitors show ~80% effective rate in lymphoma but only 10–30% in solid tumors. - Sipuleucel-T (Provenge) extends overall survival by 4.1 months in metastatic castration-resistant prostate cancer. - APMC vaccine (B16F10 cancer cell membrane-coated CpG/aluminum phosphate nanoparticles): increased DC maturation, enhanced cellular/humoral immunity, improved tumor prevention/treatment and longer mouse survival vs.
Read the article →Science Advances2022ReviewNon-viral Gene Delivery
Ann E. Metzloff, Margaret M. Billingsley, Michael J. Mitchell
mRNA vaccines have entered global use, but delivering mRNA to T cells in vivo remains challenging because T cells are non-phagocytic, reside largely in lymphoid tissues, and intravenously administered lipid nanoparticles (LNPs) tend to accumulate in the liver. There is a need for precise, scalable strategies to target mRNA to disease-specific T cells rather than all T cells, to avoid off-target inflammation and maintain self-tolerance. --- - UV-exchanged pMHCI APNs performed comparably to conventionally refolded pMHCI APNs for targeting and delivering mRNA to antigen-specific cytotoxic T cells in three mouse models. - Simultaneous targeting of three antigen-specific cytotoxic T cell populations was achieved by injecting a mixture of three UV-exchanged APNs, each carrying a different influenza A antigenic peptide. - mRNA delivery to the three antigen-specific cytotoxic T cell populations occurred at significantly higher rates compared wi
Read the article →Advanced Functional Materials2021ReviewNon-viral Gene Delivery
Zhaoting Li, Yixin Wang, Yingyue Ding, Lauren Repp, Glen S. Kwon, Quanyin Hu
Immunotherapy has limited response rates and systemic side effects, and synthetic drug delivery systems can be immunogenic and toxic. Cell-based delivery systems—using endogenous cells as natural carriers—offer low immunogenicity, low toxicity, improved biocompatibility, active tissue targeting, and the ability to cross biological barriers. This review surveys the design principles and immunotherapeutic applications of cell-based delivery systems for cancer, autoimmune diseases, and infectious diseases. --- - RBC hitchhiking: ~11.5% of drug-loaded nanoparticles carrying RBCs targeted the brain, 10× more efficient than traditional brain-targeting carriers. - Platelet-delivered aPDL1 (P-aPDL1): circulating half-life greatly increased vs free aPDL1; effectively prevented tumor recurrence and metastasis after surgery and prolonged survival in mice. - Neutrophil-carried PTX liposomes (PTX-CL/NEs): prolonged survival of glioma-bearing mice ev
Read the article →EBioMedicine* (Elsevier)2021ReviewNon-viral Gene Delivery
Ella S. Atsavapranee, Margaret M. Billingsley, Michael J. Mitchell
Adoptive T cell therapy has been revolutionized by genetic engineering, but viral transduction—the standard delivery method—has limitations including small cargo capacity, high immunogenicity, high manufacturing cost, and risks of genotoxicity/insertional mutagenesis. There is a need for improved non-viral delivery technologies to enable precise gene editing in T cells for cancer immunotherapy, especially for solid tumours and allogeneic applications. --- - Five FDA-approved CAR T cell therapies: Kymriah, Yescarta, Tecartus, Breyanzi, and Abecma. - Sleeping Beauty clinical trials: Patients with advanced NHL and ALL undergoing HSCT and CAR T cell infusion showed no acute or latent toxicities and no exacerbation of GVHD. - CRISPR/Cas9 first-in-human trial: T cells from three patients with refractory cancer were edited to remove endogenous TCRs and PD-1, achieving highly specific editing at targeted loci without clinical toxicity; edited T
Read the article →Cancer Gene Therapy* (Springer Nature America, Inc.)2021ReviewNon-viral Gene Delivery
Rakan El-Mayta, Zijing Zhang, Alex G. Hamilton, Michael J. Mitchell
CAR T cell therapies have achieved clinical success but face limitations including restriction to autologous cell sources (to avoid HLA mismatch and GvHD), cumbersome manufacturing, high costs, and poor efficacy in solid tumours. NK cells have emerged as promising alternatives because they can kill cancer cells without HLA matching, can be derived from allogeneic sources, and have the potential to become "off-the-shelf" therapeutics. However, NK cells are resistant to genetic engineering and have limited proliferation and persistence, creating a need for improved delivery technologies to maximize their therapeutic potential. --- - CAR T cell dominance: ~96.4% of 520 active CAR-based cell therapy trials globally are CAR T-cell-based; CAR-NK trials represent a very small fraction. - Retroviral transduction efficiency: 60–90% for NK-92 cells; ~50% for primary NK cells. - Electroporation: mRNA electroporation achieved 80–90% transfection in
Read the article →Exploration of Medicine2021ReviewNon-viral Gene Delivery
Sureshbabu Ram Kumar Pandian, Clayton Fernando Rencllin, Krishnan Sundar
Conventional cancer immunotherapies (checkpoint inhibitors, CAR T cells) are effective but expensive, cause adverse side effects, and face challenges in solid tumours. Nanomaterials offer advantages in delivery, diagnostics, and immune modulation, but a comprehensive understanding of how different nanomaterial types (organic, inorganic, cell membrane-based) can be integrated into cancer immunotherapy—and how their biodistribution and toxicity profiles affect clinical translation—remains needed. --- - Cationic liposomes with α-GalCer and TRP2: Enhanced IFN-γ secretion, cytotoxic T-cell activation, and reduced tumour survival; PEG-coating reduced cytotoxicity. - PLGA nanoparticles with TLR ligands and antigen: Improved antibody and T-cell responses compared to soluble antigen plus adjuvants, resembling live viral vaccine immunogenicity. - Pyruvate dehydrogenase E2 nanoparticles with CpG and gp100: 1.5-fold increase in CD8+ T cells and 5-f
Read the article →Nature Reviews Drug Discovery2021ReviewDrug Delivery
Michael J. Mitchell, Margaret M. Billingsley, Rebecca M. Haley, Marissa E. Wechsler, Nicholas A. Peppas, Robert Langer
Nanoparticle (NP) research has generated promising preclinical results, but clinical translation remains limited. A major barrier is the mismatch between one-size-fits-all NP designs and the heterogeneous biological barriers across patients and diseases. Precision medicine offers patient stratification, but precision therapies still face delivery barriers. This review argues that intelligent NP design can overcome these barriers and improve both general and precision therapeutic outcomes. --- - Tumor accumulation: Meta-analysis of 232 datasets found that, on average, only 0.7% of injected NP doses reach tumors. - EPR effect variability: Up to 10–15% of injected NPs accumulate at tumor sites in some studies, compared with 0.1% of free drug; however, EPR is highly heterogeneous. - Targeted NP limitation: Antibody-targeted NPs interacted with only 2% of tumor cells in one study. - iCluster system: Inhibited tumor growth by up to 95% in viv
Read the article →Angewandte Chemie International Edition2020ReviewNon-viral Gene Delivery
Shuangqian Yan, Zichao Luo, Zhenglin Li, Yu Wang, Jun Tao, Changyang Gong, Xiaogang Liu
Cancer immunotherapy has improved clinical outcomes, but few patients show adequate response rates and long-term responses, and systemic side effects remain common due to the dynamic nature of the immune system. Biomaterial-assisted immunotherapy is a promising approach to improve therapeutic efficacy and reduce side effects. --- - DNA–RNA nanocapsules: augmented neoantigen-specific peripheral CD8+ T cell responses more than 8-fold relative to CpG controls and prevented growth of neoantigen-specific colorectal tumors. - Nanovaccine: OVA/ICG nanovaccines showed high antigen-loading efficiency of 80.8% and enabled imaging-guided photothermal immunotherapy. - STING nanoparticles: pH-responsive polymer nanoparticles delivering cGAMP potently inhibited B16F10 growth by stimulating an immunogenic, T-cell-inflamed tumor microenvironment. - Liposome platform HMME/R837@Lip: combined with checkpoint blockade inhibited tumor growth and metastases
Read the article →PNAS* (*Proceedings of the National Academy of Sciences*)2020ReviewNon-viral Gene Delivery
Stephany Y. Tzeng, Kisha K. Patel, David R. Wilson, Randall A. Meyer, Kelly R. Rhodes, Jordan J. Green
Cancer immunotherapy has shown clinical success but remains limited by low response rates, high cost, and the need for ex vivo cell manipulation or prior knowledge of patient-specific tumor antigens. A broadly applicable, antigen-agnostic strategy that genetically reprograms tumor cells in situ—without ex vivo cellular manufacturing—could reduce cost and broaden accessibility. ---
Read the article →Oncology Reports2019ReviewNon-viral Gene Delivery
Rimjhim Mohanty, Chitran Roy Chowdhury, Solomon Arega, Prakriti Sen, Pooja Ganguly, Niladri Ganguly
Cancer is a leading cause of mortality worldwide, and conventional treatments and cytotoxic immunotherapies have limitations. Because tumors are complex and involve multiple genetic and cellular factors in tumorigenesis and metastasis, there is a need for an immunotherapy that targets tumors at both cellular and genetic levels. CAR T cell therapy has emerged as a novel T cell engineering practice, and this review synthesizes its advantages, advances, and differences from chemotherapy and radiotherapy. --- - CAR T cell therapy achieved remission rates of up to 80% in hematologic cancers, particularly ALL and non-Hodgkin lymphomas. - Second-generation anti-CD19 CARs achieved complete remission rates of up to 90% in patients with recurrent B-cell ALL. - ELIANA trial: tisagenlecleucel produced a 3-month complete remission rate of 83% and a 6-month survival rate of 89%. - ZUMA-1 trial: axicabtagene ciloleucel produced an 82% overall response
Read the article →Nature Reviews Drug Discovery.2019ReviewNon-viral Gene Delivery
Rachel S. Riley, Carl H. June, Robert Langer, Michael J. Mitchell.
Immunotherapy has become powerful but broad implementation limited by inability to control immune modulation; serious adverse effects including autoimmunity, nonspecific inflammation. Need delivery technologies to improve efficacy and safety. Numbers.
Read the article →Theranostics2017ReviewNon-viral Gene Delivery
Chao Wang, Wujin Sun, Yanqi Ye, Hunter N. Bomba, Zhen Gu
Immune cell/organ therapies based on manipulation, infusion, and implantation of autologous or allogeneic cells/organs are costly, time-consuming, and sometimes limited in clinical effectiveness. Biomimetic materials and strategies offer an alternative by enabling artificial immune cells and lymphoid organs that are ready-to-use and scalable for immunotherapy. --- - PLGA aAPCs with anti-CD3, anti-CD28, pMHC, and encapsulated IL-2 showed stable ligand presentation for ~20 days, significant IFN-γ secretion, and 45-fold T cell expansion; 6–10 μm particles were most effective. - Ellipsoidal PLGA aAPCs were more efficient than spherical particles; nanoellipsoidal aAPCs stimulated stronger in vivo immune responses at reduced protein dose and showed enhanced pharmacokinetics. - Filamentous anti-CD3 polymers induced more robust T cell responses than PLGA microparticles due to structural flexibility and multivalency. - Magnetic nano-aAPCs with a
Read the article →Pharmaceutical Research2011ReviewNon-viral Gene Delivery
Wei-Yun Sheng, Leaf Huang
The immune system can recognize and kill pre-cancer and cancer cells, but surviving tumor cells learn to escape immune surveillance after immunoselection. Cancer immunotherapy aims to overcome these escape mechanisms. Nanomedicine offers tools—nanodiagnostics and nanobiopharmaceuticals—to deliver antigens, adjuvants, cytokines, and nucleic acids, and to target immune cells or the tumor microenvironment, potentially improving the efficacy of cancer immunotherapy. --- - G3139-LNP (CpG ODN against Bcl-2 encapsulated in lipid nanoparticles): enhanced IFN-γ, IL-2, IL-4, and IL-10 by ~4-fold; significantly enlarged spleen; inhibited tumor growth by >50%; prolonged host survival by 245%. - IL-18 + liposomal doxorubicin combination: 22% of mice remained tumor-free for 6 months vs 0% for either monotherapy in an ID8 ovarian tumor model. - Sipuleucel-T (Provenge®): first FDA-approved cancer therapeutic vaccine (April 2010); in phase III, extended
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