Molecular therapy. Nucleic acids2026ResearchNon-viral Gene DeliveryDrug Delivery
Ramamurthy A, Scimonelli G, Murphy Wl, Saha K
Human T cells modified with nucleic acids constitute a powerful and emerging therapeutic modality for cancer, autoimmune disorders, and aging-related diseases. However, delivering nucleic acids, such as mRNA encoding synthetic receptors, transcription factors, cytokines, or genome editors to T cells can be…
Read the article →Nature Communications2023ResearchNon-viral Gene Delivery
Yue Wang, Shi-Kun Zhou, Yan Wang, Zi-Dong Lu, Yue Zhang, Cong-Fei Xu, Jun Wang
PD-1/PD-L1 blockade therapy is successful but often yields poor benefits due to insufficient T-cell infiltration and low intratumoral concentrations of PD-1/PD-L1 inhibitors. While strategies exist to increase either T-cell recruitment or inhibitor delivery, none actively recruit T cells while achieving…
Read the article →Advanced Science2023ResearchNon-viral Gene Delivery
Cheng Huang, Xing Duan, Jichao Wang, Qingqing Tian, Yangmei Ren, Kepan Chen, Zongliang Zhang, Yuanyou Li, Yunyu Feng, Kunhong Zhong, Yuelong Wang, Liangxue Zhou, Gang Guo, Xiangrong Song, And Aiping Tong
Bispecific T-cell engagers (BiTEs) are promising but require large amounts of purified protein, have high manufacturing costs, poor in vivo stability, and short serum half-lives. mRNA delivery could enable continuous endogenous production of BiTEs, but efficient and safe delivery systems are needed. The study…
Read the article →Science2022ResearchNon-viral Gene Delivery
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…
Read the article →Science Advances2022ResearchNon-viral Gene Delivery
Rasheid Smith, Emad I. Wafa, Sean M. Geary, Kareem Ebeid, Suhaila O. Alhaj-Suliman, Aliasger K. Salem
Cancer vaccines as monotherapies have displayed limited clinical success due to the immunosuppressive tumour microenvironment (TME). Nanoscale formulations can enhance vaccine efficacy by combating TME immunosuppression, but there is a need for novel adjuvant formulations that can be combined with therapeutic cancer…
Read the article →Journal of Controlled Release 347 (2022ResearchNon-viral Gene Delivery
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…
Read the article →Biomaterials 281 (2022ResearchNon-viral Gene Delivery
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…
Read the article →Nature Biomedical Engineering2021ResearchNon-viral Gene Delivery
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…
Read the article →Leukemia2021ResearchDrug Delivery
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 tumour escape and relapse. A modular…
Read the article →Drug Delivery and Translational Research2021ResearchDrug Delivery
Yuan Rui, Jordan J. Green
Glioblastoma (GBM) is one of the deadliest primary adult tumours 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 tumours, the blood-brain barrier (BBB) and the immune-privileged…
Read the article →Molecular Therapy2021ResearchNon-viral Gene Delivery
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…
Read the article →Biotechnology and Bioengineering (accepted manuscript)2021ResearchNon-viral Gene Delivery
Emily Harris, Devon Zimmerman, Eric Warga, Anil Bamezai, Jacob Elmer
Retroviral gene delivery for T cell therapies is expensive, semi-randomly integrating, and variable between patients. Non-viral alternatives are needed, but T cells are notoriously hard to transfect, especially primary T cells. Lipofectamine LTX was the best vehicle in Jurkat cells; optimised conditions in X-VIVO…
Read the article →Nature Communications2021ResearchNon-viral Gene Delivery
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…
Read the article →Acta Biomaterialia (Published by Elsevier Ltd on behalf of Acta Materialia Inc.)2020ResearchNon-viral Gene Delivery
Kelly R. Rhodes, Randall A. Meyer, Justin Wang, Stephany Y. Tzeng, Jordan J. Green
Regulatory T cell (Treg)-based therapeutics show promise for treating autoimmune diseases and preventing transplant rejection, but adoptive Treg transfer is expensive, complex, and difficult to implement. "Off-the-shelf" non-cellular alternatives that can induce endogenous Tregs in vivo are needed. Existing…
Read the article →Applied Materials Today2020ResearchNon-viral Gene Delivery
Jing Zhao, Danping Lu, Sergio Moya, Haoying Yan, Miaojuan Qiu, Junzong Chen, Xincheng Wang, Yang Li, Haobo Pan, Guochuang Chen, Guocheng Wang
Bispecific T-cell engager (BiTE) immunotherapy is a promising cancer treatment, but clinical application is limited by high production costs and short in vivo half-life of BiTE proteins. A gene delivery system that enables sustained in vivo expression of BiTE could overcome these limitations, but existing non-viral…
Read the article →ACS Applied Materials & Interfaces2020ResearchNon-viral Gene Delivery
Kwang-Soo Kim, Jun-Hyeok Han, Seung Hee Choi, Hae-Yun Jung, Joo Dong Park, Hee-Jung An, Seong-Eun Kim, Dong-Hyun Kim, Junsang Doh, Dong Keun Han, Ik-Hwan Kim, Wooram Park, Kyung-Soon Park
Natural killer (NK) cells are promising for cancer immunotherapy due to their lower risk of cytokine storm and graft-versus-host disease compared to T cell therapies. However, existing NK cell activation strategies—genetic engineering and cytokine treatment—are inefficient, expensive, and involve complex processing…
Read the article →Molecular Therapy2020ResearchNon-viral Gene Delivery
Xiaojing Shi, Qinqin Cheng, Tianling Hou, Menglu Han, Goar Smbatyan, Julie E. Lang, Alan L. Epstein, Heinz-Josef Lenz, Yong Zhang
Exosomes are nanosized membranous vesicles with unique properties (abundant membrane proteins, high biocompatibility, low immunogenicity) that make them attractive for therapeutic development. While exosomes have been studied as drug delivery vehicles, fewer studies have focused on engineering exosome surface…
Read the article →Nature Communications2020ResearchNon-viral Gene Delivery
N.N. Parayath, S.B. Stephan, A.L. Koehne, P.S. Nelson, M.T. Stephan
CAR T and TCR T cell therapies are powerful but face prohibitive costs and manufacturing complexity due to the need for leukapheresis, ex vivo transduction, expansion, and quality control—all under GMP conditions. An "off-the-shelf" injectable nanocarrier that can transiently reprogram circulating T cells in vivo…
Read the article →Nature Communications2020ResearchNon-viral Gene Delivery
John C. Charpentier, Di Chen, Philip E. Lapinski, Jackson Turner, Irina Grigorova, Joel A. Swanson, Philip D. King
Macropinocytosis has been shown to regulate the growth of Ras-transformed tumour cells under amino acid (AA)-limiting conditions by providing extracellular proteins that are degraded into AA to fuel cell growth and activate mTORC1. However, whether macropinocytosis regulates the growth of non-transformed mammalian…
Read the article →Cancer Immunology Research (AACR)2020ResearchNon-viral Gene Delivery
Dylan J. Drakes, Sarwish Rafiq, Terence J. Purdon, Andrea V. Lopez, Smita S. Chandran, Christopher A. Klebanoff, Renier J. Brentjens
T-cell receptor (TCR)-modified T-cell gene therapy can target a variety of extracellular and intracellular tumour-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation in vivo, particularly when tumour cells downregulate…
Read the article →Proceedings of the National Academy of Sciences (PNAS)2020ResearchNon-viral Gene Delivery
Bradley Vis, Rachel E. Hewitt, Tom P. Monie, Camilla Fairbairn, Suzanne D. Turner, Stephen D. Kinrade, Jonathan J. Powell
Ultrasmall silica nanoparticles (USSN, <10 nm diameter) were recently shown to stimulate T lymphocytes directly at relatively low exposure doses, but the underlying mechanisms and associated cell signalling were unknown. Understanding whether USSN directly engage the T cell receptor (TCR) complex or act through other…
Read the article →Angewandte Chemie International Edition2020ResearchNon-viral Gene Delivery
Xuewei Zhao, Jinjin Chen, Min Qiu, Yamin Li, Zachary Glass, Qiaobing Xu
In vivo engineering of T lymphocytes is limited by poor transfection efficiency and reliance on ex vivo electroporation. A non-viral mRNA delivery platform that can target primary T cells in vivo is needed for CAR T-cell therapy, vaccines, and immunotherapy. Rough screening identified imidazole head 93 with O17O…
Read the article →Bioconjugate Chemistry2020ResearchNon-viral Gene Delivery
Margaret M. Billingsley, Nathan Singh, Pranali Ravikumar, Rui Zhang, Carl H. June, Michael J. Mitchell
CAR T cell therapy currently relies on viral vectors or electroporation for T cell engineering. Viral vectors cause permanent CAR expression and carry safety/manufacturing limitations, while electroporation is cytotoxic and requires specialised equipment. A safer, efficient non-viral mRNA delivery platform for human…
Read the article →Journal of Materials Chemistry B2020ResearchNon-viral Gene Delivery
Yana Tarakanchikova, Albert Muslimov, Igor Sergeev, Kirill Lepik, Nikita Yolshin, Alexander Goncharenko, Kirill Vasilyev, Igor Eliseev, Anton Bukatin, Vladislav Sergeev, Sergey Pavlov, Alexey Popov, Igor Meglinski, Boris Afanasyev, Bogdan Parakhonskiy, Gleb Sukhorukov, Dmitry Gorin
DNA- and mRNA-based therapies are transforming biomedicine, but intracellular delivery—especially to hard-to-transfect, clinically relevant cells such as primary human T lymphocytes—remains a major barrier. Existing non-viral methods often suffer from low transfection efficiency, high toxicity, or complex…
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