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.
CAR T cell therapy is FDA/EMA-approved for B cell malignancies and multiple myeloma, but manufacturing relies on viral vectors—associated with safety concerns, high cost, and production challenges—or electroporation, which can be highly cytotoxic. Nanosystems may offer a safer, cost-effective alternative, but T cells are difficult to transfect, so rational design of lipid- and polymer-based carriers is urgently needed. Si-PDMAEMA-pDNA achieved 46% transfection in Jurkat cells and 44% in primary human T cells; pDNA/PEI-based systems reached 51% in Jurkat and 60% in primary human T cells. - pIAE + anti-CD3 + PiggyBac transposon.
CAR-T cell therapy has shown impressive success in hematological malignancies, but systemic toxicity (CRS, ICANS, on-target/off-tumor effects) and the complex, costly, individualized manufacturing process of autologous CAR-T cells hinder broader application. Universal allogeneic CAR-T cells have encountered safety concerns, with FDA halting some clinical trials. There is an urgent need for new strategies to overcome these barriers. --- - In vivo CAR-T induction with PBAE nanoparticles: Matthias Stephan's team achieved stable and transient expression of CD19-specific CAR in T cells via CAR-DNA and CAR-mRNA nanoparticles, respectively. Antitumor efficacy comparable to conventional lab-manufactured CAR-T cells without systemic toxicity. - Lentiviral in vivo CAR-T: Buchholz and colleagues induced in situ CAR-T cells in NSG mice with antitumor activity, but observed CRS and unexpected CAR-positive NK and NKT cells due to non-specific lentivi
Joel G. Rurik, István Tombácz, Amir Yadegari, Pedro O. Méndez Fernández, Swapnil V. Shewale, Li Li, Toru Kimura, Ousamah Younoss Soliman, Tyler E. Papp, Ying K. Tam, Barbara L. Mui, Steven M. Albelda, Ellen Puré, Carl H. June, Haig Aghajanian, Drew Weissman, Hamideh Parhiz, Jonathan A. Epstein
Fibrosis affects millions of people with cardiac disease and contributes to heart failure. While adoptive transfer of CAR T cells targeting fibroblast activation protein (FAP) has shown promise in reducing cardiac fibrosis, conventional CAR T cells persist for months to years and could cause chronic off-target toxicity by continuously attacking fibroblasts throughout the body, impairing wound healing.[reference:0][reference:1] A method to. ### LNP Characterization & In Vitro CAR Expression | Parameter | Result | |---------------|------------| | LNP hydrodynamic diameter | ~80 nm[reference:49] | | Polydispersity index | 0.02-0.06[reference:50] | | mRNA.
Savan K. Patel, Margaret M. Billingsley, Caitlin Frazee, Xuexiang Han, Kelsey L. Swingle, Jingya Qin, Mohamad-Gabriel Alameh, Karin Wang, Drew Weissman, Michael J. Mitchell
mRNA delivery to T cells could enable ex vivo and in vivo T cell engineering, but LNPs still face poor extrahepatic delivery, endosomal recycling, and limited T cell transfection. Cholesterol analogs such as hydroxycholesterols may alter NPC1 recognition and endosomal trafficking, providing a route to improve T cell mRNA delivery. In primary human T cells, A1-25 and A1-50 improved mRNA delivery by 1.8-fold and 2.0-fold, respectively, vs S2. - In Jurkat cells, A1-25, A1-50, and B1-50 increased luciferase expression 2.1-fold, 1.9-fold, and.
Immunotherapy has improved outcomes in cancer and infectious disease, but off-target effects, systemic toxicities, and variable efficacy remain limiting. Nanoscale engineering offers ways to manipulate immune cell functions—enhancing immunity against cancers and pathogens, controlling the site of immune response, and promoting tolerance—by tuning nanoparticle size, shape, charge, and surface chemistry. CL4H6 lipid nanoparticles silenced STAT3 and HIF-1α in tumor-associated macrophages by 37% and 48%, respectively, increased M1 markers, reduced tumor size, and altered cytokine profiles in a B16-F10 model. -.
Paolo Morfino, Alberto Aimo, Vincenzo Castiglione, Carolina Galvez-Montón, Michele Emdin, Antoni Bayes-Genis
Cardiac fibrosis contributes to the pathogenesis of heart failure, myocardial infarction, and arrhythmias, but no primarily anti-fibrotic drug has been approved for cardiovascular disease. Many candidate anti-fibrotic strategies have shown promise in preclinical models yet failed to demonstrate clear clinical benefit. There is a need to summarize current and emerging therapeutic options and to evaluate a new approach: targeting cardiac. RAAS inhibitors: Lisinopril reduced collagen volume fraction (CVF) vs. hydrochlorothiazide; losartan reduced CVF and PICP; spironolactone/eplerenone reduced PICP/PIIINP and improved diastolic function in some trials. -.
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.
Farough Marofi, Roza Motavalli, Vladimir A. Safonov, Lakshmi Thangavelu, Alexei Valerievich Yumashev, Markov Alexander, Navid Shomali, Max Stanley Chartrand, Yashwant Pathak, Mostafa Jarahian, Sepideh Izadi, Ali Hassanzadeh, Naghmeh Shirafkan, Safa Tahmasebi, Farhad Motavalli Khiavi
CAR T cell therapy has transformed treatment of hematologic malignancies, but its efficacy in solid tumors remains unsupported. Solid tumors present distinct barriers—antigen heterogeneity, poor T cell trafficking/infiltration, and an immunosuppressive tumor microenvironment (TME)—that limit CAR T cell function. This review addresses these barriers and evaluates emerging strategies to improve CAR T cell therapy in non-hematologic malignancies. --- - Ovarian cancer: MSLN-CAR NK cells significantly killed MSLN⁺ ovarian cancer cells (SK-OV-3, OVCAR-3) *in vitro*. MUC16-specific CAR T cells eradicated malignant cells in mouse models. TAG72-CAR T and FRα-CAR T inhibited ovarian cancer growth. - Breast cancer: MUC28z CAR T cells (targeting tMUC1) reduced TNBC tumor proliferation and survival in a xenograft model. HRG1β-based CAR T cells inhibited breast cancer via HER family receptors. Anti-HER2 CAR T cells triggered cell death in HER2-overex
CAR-T cell therapy has produced remarkable clinical responses in certain B cell leukemias and lymphomas, but major limitations remain—including life-threatening toxicities, limited efficacy in solid tumors, antigen escape, poor persistence/trafficking, and an immunosuppressive microenvironment. This review addresses these barriers and discusses recent innovations in CAR-T engineering to improve efficacy and safety in both hematological malignancies and solid tumors. --- - Antigen escape: 70–90% of relapsed/refractory ALL patients show durable responses to CD19 CAR-T, but 30–70% of recurrent disease involves CD19 downregulation/loss. BCMA loss also observed in multiple myeloma. - Dual targeting: CD19/CD22 and CD19/BCMA dual-targeted CAR-T cells show promising efficacy and favorable safety in early clinical trials. Tandem HER2/IL13Rα2 CARs improved anti-tumor activity and decreased antigen escape in glioblastoma models. - Toxicity reducti
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
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
Ian C. Miller, Ali Zamat, Lee-Kai Sun, Hathaichanok Phuengkham, Adrian M. Harris, Lena Gamboa, Jason Yang, John P. Murad, Saul J. Priceman, Gabriel A. Kwong
CAR T cell therapy for solid malignancies typically results in poor responses. Systemic administration of immunomodulatory biologics (cytokines, BiTEs) can augment T cell activity but off-target toxicity narrows the therapeutic window. A method to spatially and temporally control transgene expression by engineered T cells at tumor sites—without systemic exposure—could improve safety and efficacy. ### Thermal Switch Engineering | Parameter | Result | |---------------|------------| | Best HSE repeat number | 7 repeats (5H-7H best; 2H-4H lower response) | | Best core promoter | YB (synthetic) — ~60-fold induction.
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.
Hamideh Parhiz, Jacob S. Brenner, Et Al. (full Author List Not Included In The Supplied Excerpt)
T cells are notoriously resistant to exogenous mRNA transfection, limiting in vivo T cell engineering for immunotherapy, CAR T generation, and HIV cure. A safe, specific, and efficient in vivo mRNA delivery platform for CD4+ T cells was needed. In vitro: anti-CD4/mRNA-LNPs bound specifically to human CD4+ T cells; ~80% of CD3+CD8− splenocytes became ZsGreen1+ with anti-CD4/Cre mRNA-LNPs, even at the lowest dose. - In vivo biodistribution: spleen uptake was.
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,.
Adoptive T cell therapy has revolutionized treatment of some hematologic malignancies but remains limited in solid tumors—especially central nervous system (CNS) tumors—by poor intratumoral delivery across anatomical barriers, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction caused by immunosuppressive tumor microenvironments. Nanoparticles may overcome these limitations by improving ex vivo T cell manufacture. Representative findings from cited studies: - Nanostructured PEG hydrogels with anti-CD3-conjugated gold nanoparticles enabled T cell activation, proliferation, and memory. - Immunoliposomes targeting CD90 delivered a.
Est-Witte Se, Livingston Nk, Omotoso Mo, Green Jj, Schneck Jp.
T cell therapies (TIL, TCR, CAR T) show clinical efficacy but are limited by high cost, lengthy ex vivo manufacturing, patient variability, and poor persistence. Nanoparticles offer a modular, universal platform to improve T cell therapy at every stage—from antigen presentation and T cell activation to T cell maintenance—while reducing cost and broadening patient accessibility. Nano-aAPC E+E expanded Kb-TRP2 cognate cells from ~0.03% to 17.6% by day 7; nano-aAPCs expanded MART-1-specific CD8⁺ T cells more effectively than autologous DCs and CD3/CD28 Dynabeads, with higher stem cell memory.
Annika M. Frank, Angela H. Braun, Lea Scheib, Shivani Agarwal, Irene C. Schneider, Floriane Fusil, Severine Perian, Ugur Sahin, Frederic B. Thalheimer, Els Verhoeyen, Christian J. Buchholz
Conventional lentiviral vectors (LVs) are not selective for T cells and cannot efficiently transduce resting or minimally stimulated T lymphocytes, which limits their use for direct in vivo T-cell gene delivery. There is a need for vectors that can both target T cells specifically and activate them sufficiently to permit gene transfer without prior ex vivo activation. --- - Selectivity: CD3-LVs transduced CD3(^+) Jurkat cells but not CD3(^-) Molt4.8 cells. VSV-LV transduced HUVEC (86.74%), HepG2 (32.53%), and Nalm-6 (97.50%) cells, whereas CD3-LVs showed <0.3% transduction in these off-target cells. - Nonactivated T cells: CD3-LVs transduced freshly isolated PBMCs in the absence of cytokines or with IL-2 or IL-7/IL-15 at efficiencies similar to peak activation. VSV-LV was substantially less efficient under these conditions. - Whole blood: CD3-LVs mediated T-cell gene transfer in whole blood without additional stimuli. VCNs: TR66-LV 1.17
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
