Every entry summarises what the study set out to test, what it found and why it changes how we design delivery systems. Browse research and reviews or search the collection.
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
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.
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
Azadeh Kheirolomoom, Aris J. Kare, Elizabeth S. Ingham, Ramasamy Paulmurugan, Elise R. Robinson, Mo Baikoghli, Mohammed Inayathullah, Jai W. Seo, James Wang, Brett Z. Fite, Bo Wu, Spencer K. Tumble, Marina N. Raie, R. Holland Cheng, Lisa Nichols, Alexander D. Borowsky, Katherine W. Ferrara
Ex vivo T-cell engineering is effective but complex, costly, and difficult to scale. A method to transfect T cells directly in situ could simplify T-cell immunotherapy, but T-cell targeting may also trigger activation, depletion, cytokine release, and phenotypic changes that must be understood. In vitro: >80% of Jurkat cells expressed mCherry with 16% aCD3-LNPs; ~97% became CD69⁺; aCD3 coating caused T-cell depletion and CD3e internalization. - In vivo 24 h: aCD3-LNPs transfected ~2–4% of splenic T cells and.
mRNA is a promising cancer immunotherapy platform for vaccines, cytokines, costimulatory receptors, and therapeutic antibodies, but it is unstable, immunogenic, and poorly delivered in vivo. Safer and more efficient delivery systems are needed to improve mRNA stability, cellular uptake, endosomal escape, and tumor-site accumulation. PL1 LNPs delivering CD137 or OX40 mRNA to tumor-infiltrating T cells, combined with anti-OX40 antibody, showed more significant antitumor activity than anti-OX40 antibody alone in multiple tumor models. -.
mRNA is an attractive platform for cancer immunotherapy, but its instability, susceptibility to RNase degradation, and inefficient endosomal escape limit therapeutic applications. Lipid-based nanocarriers are non-viral vectors that can protect mRNA, improve transfection, and deliver it to intracellular compartments suitable for translation. Optimal pKa for ionizable lipids: 6.2–6.5 for intravenous mRNA delivery; 6.6–6.9 for intramuscular mRNA delivery. - Modifying lipid-to-mRNA ratio can shift lipoplex charge: anionic lipoplexes target spleen, cationic.
Cancer immunotherapy — especially immune checkpoint inhibitors (ICIs), CAR-T cells, and oncolytic viruses (OVs) — has shown major clinical success but still faces low response rates, severe immune-related side effects, complex tumor microenvironment barriers, instability/short half-life of therapeutics, and high manufacturing costs. Polymeric systems are proposed as versatile carriers and immune-modulating platforms to improve targeting, safety. Representative findings highlighted in the review: - ICI delivery: Folate-PEI/PD-L1 siRNA blocked PD-1/PD-L1 interactions and reduced PEI cytotoxicity in ovarian cancer cells. PLGA-PEG nanoparticles targeted to CD8⁺ T.
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
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
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
Kinan Alhallak, Jennifer Sun, Katherine Wasden, Nicole Guenthner, Julie O'neal, Barbara Muz, Justin King, Daniel Kohnen, Ravi Vij, Samuel Achilefu, John F. Dipersio, Abdel Kareem Azab
T-cell-based immunotherapies such as CAR-T cells and bispecific T-cell engagers (BiTEs) have shown promise but have significant limitations: (1) poor pharmacokinetics requiring continuous infusion (BiTE half-life ~2 h), and (2) single-antigen targeting leading to antigen-loss tumor escape and relapse. A modular nanoparticle platform that addresses both limitations—extending half-life and enabling multispecific targeting—could improve efficacy. ### Nanoparticle Characterization & Pharmacokinetics | Parameter | Result | |---------------|------------| | Liposome size | ~100 nm | | Half-life (non-PEGylated nanoBiTE) | ~36 h | | Half-life (PEGylated nanoBiTE) |.
Glioblastoma (GBM) is one of the deadliest primary adult tumors with a median survival of only 14.6 months post-diagnosis, a statistic that has changed little in two decades. While cancer immunotherapy has shown remarkable progress in other solid tumors, the blood-brain barrier (BBB) and the immune-privileged status of the central nervous system pose unique drug delivery obstacles. A comprehensive understanding of physiological, immunological ### Transport Barriers | **Barrier** | **Key Finding** | |-------------|-----------------| | BBB | Passive transport limited to <400 Da or lipid-soluble molecules; all GBM patients have tumor regions with.
Julia Koerner, Dennis Horvath, Valerie L. Herrmann, Anna Mackeracher, Bruno Gander, Hideo Yagita, Jacques Rohayem, Marcus Groettrup
Cancer immunotherapy needs potent, pharmaceutically defined, GMP-compatible adjuvants for clinical translation. Poly(I:C) is a widely used TLR3 agonist but has ill-defined structure, heterogeneity, pyrogen contamination, and toxicity concerns. Riboxxim is a well-defined 100-bp double-stranded RNA with a 5′-triphosphate moiety that activates both endosomal TLR3 and cytosolic RIG-I. PLGA particles can co-deliver antigen and adjuvant to dendritic. Particle properties: MPs ~1–1.5 µm; NPs ~250 nm; negative zeta potential; OVA release burst within 24 h followed by sustained release. MPs showed better release profile than NPs. - Route comparison: Subcutaneous.
mRNA vaccines have progressed from a scepticism-inducing idea to clinical reality, with COVID-19 catalysing the fastest vaccine development in history. Remaining needs include optimizing mRNA design, intracellular delivery, and applications beyond SARS-CoV-2 prophylaxis. This review describes mRNA vaccine technologies, with emphasis on lipid nanoparticles and other non-viral delivery vehicles. BNT162b2: 95% overall efficacy in phase III (43,548 participants); real-world Israel data: 94% against symptomatic COVID-19, 87% against hospitalization, 92% against severe disease; 90–100% efficacy across subgroups. -.
Gong N, Sheppard Nc, Billingsley Mm, June Ch, Mitchell Mj.
T-cell-based immunotherapies have shown clinical success in B-cell malignancies, but broad implementation is limited by insufficient T-cell expansion, poor trafficking into solid tumours, T-cell exhaustion in hostile tumour microenvironments, and loss of target antigen expression. Nanomaterials may uniquely overcome these barriers through rational design. IL-2-Fc fusion-protein-modified liposomes delivered to the surface of >95% of adoptively transferred T cells, inducing enhanced T-cell proliferation in tumour-bearing mice. - IL-15 superagonist nanogel backpacked onto.
Cancer immunotherapy has shown efficacy but is limited by serious adverse effects, nonspecific inflammation, and challenges in spatiotemporal control of immune responses. Nanomedicine and functionalized nanosystems offer programmable pharmacokinetics, co-delivery of immunomodulators, and targeted delivery, potentially improving immunotherapy outcomes. Antigen-capturing NPs (AC-NPs) plus αPD-1 improved cure rate by 20% in B16F10 melanoma, expanded CD8⁺ cytotoxic T cells, and increased CD4⁺/Treg and CD8⁺/Treg ratios. - Cationic lipid-assisted PEG-b-PLGA NPs (CLANs).
Cervical cancer is immunologically relevant because retained high-risk HPV antigens can be recognized as foreign, making immunotherapy attractive. However, conventional immunotherapy is limited by variable efficacy, immune evasion, cytokine toxicity, and poor targeting. Nanomedicine may improve delivery, targeting, pharmacokinetics, and safety of immunotherapeutic agents. Pembrolizumab showed increased activity in cervical cancer in KEYNOTE-158 and promising antitumor activity in phase Ib KEYNOTE-028. - Nivolumab in phase II NRG-GY002: minimal response rate, median survival 14.5 months,.
Raza F, Zafar H, Zhang S, Kamal Z, Su J, Yuan W-E, Qiu M.
Cancer immunotherapy is limited by the immunosuppressive tumor microenvironment, patient heterogeneity, poor delivery of immunotherapeutics, and systemic immunotoxicity. Cell membrane-derived biomimetic nanoparticles may improve delivery and biodistribution, enhance targeting and immune stimulation, and overcome barriers faced by conventional nanomedicine. RBCM-coated nanoparticles improved half-life by up to 50% versus PEGylated nanoparticles and were detected in blood circulation after 72 h. - A size-reducible RBCM biomimetic system combined with.
mRNA vaccines are promising but naked mRNA is fragile, susceptible to enzymatic degradation, poorly taken up by cells due to electrostatic repulsion, and can trigger innate immune responses. Self-assembly offers a versatile approach to prepare delivery vehicles with customizable properties. The review discusses design and self-assembly of mRNA vaccines, materials commonly used, physicochemical characteristics, routes of administration, and. BNT162b2: 95.0% efficacy in phase III (8 COVID-19 cases in vaccine group vs 162 in placebo); 94.6% efficacy including prior infection; ~52% efficacy between first and second dose. - mRNA-1273: 94.1% efficacy in phase.
Tumor microenvironment (TME) modulation is a promising strategy in cancer immunotherapy, but conventional immunotherapeutic agents suffer from limited drug retention in the TME, severe adverse events, and low response rates. Nanoparticles can prolong retention, enable targeted delivery to TME components, and convert the immunosuppressive TME into an immunosupportive state, potentially improving therapeutic efficacy while reducing toxicity. DC targeting: CD40-targeted PLGA nanoparticles achieved highest binding/uptake and maximum IL-12 production in vitro; however, T cell proliferation was driven mainly by TLR ligands rather than targeting ligand. -.
mRNA has therapeutic potential for vaccines, protein replacement, cancer immunotherapy, cellular reprogramming, and genome editing, but it requires safe, effective, and stable delivery systems to protect it from degradation and enable cellular uptake and mRNA release. Lipid nanoparticles have entered the clinic for mRNA delivery, most notably in COVID-19 mRNA vaccines. COVID-19 mRNA vaccines mRNA-1273 and BNT162b2 showed ~95% efficacy in phase III trials and use ionizable LNPs (SM-102 and ALC-0315, respectively). - Influenza mRNA-1440: 100 µg dose induced 78.3% HAI and 87.0% MN.
mRNA therapeutics are limited by innate immune activation, rapid RNase degradation, and inefficient delivery to target organs. Although LNPs are the only clinically approved RNA therapeutic carriers, most systemically delivered LNPs accumulate in the liver, so organ-specific delivery remains a major barrier for protein replacement, cancer immunotherapy, and gene editing. LNPs are the only RNA therapeutic carriers approved for clinical use at the time of the review. - PEG content from 1% to 5% produces LNPs approximately 100 nm to 20 nm in size; 0.5% PEG gave highest subretinal.
Cancer immunotherapy can produce durable clinical responses, but systemic delivery of immunostimulatory agents is limited by short half-lives, off-target toxicities (e.g., cytokine release syndrome), low response rates (10–30%), and poor efficacy in solid tumors. Polymeric micelles offer a biocompatible, modifiable, core–shell delivery platform that can improve bioavailability, enable tumor accumulation via the EPR effect, and reduce systemic. IL-2 micelles: Enhanced DC vaccine efficacy and increased antigen-specific CTL accumulation at tumor sites. - PMet-P(cdmPEG2K) micelles: Co-delivery of DOX and pIL-12 was more effective at inhibiting tumor growth than.
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
