Journal of controlled release : official journal of the Controlled Release Society2026ResearchNon-viral Gene DeliveryDrug Delivery
Kim M, Jeong M, Chatterjee S, Vaidya A, Pham C, Lee Sm, Et Al.
Fibroblast activation and differentiation into myofibroblasts drive excessive extracellular matrix deposition and irreversible scarring in pulmonary fibrosis, such as idiopathic pulmonary fibrosis (IPF), underscoring the need for therapies that directly target fibroblast activation. Here, we apply engineered…
Read the article →Molecular pharmaceutics2026ResearchNon-viral Gene DeliveryDrug Delivery
Kc R, Nasrullah M, Meenakshi Sundaram Dn, Patel D, Sandhu G, Kucharski C, Et Al.
Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) has long been identified as a promising therapeutic due to its ability to induce apoptosis selectively in cancer cells. However, poor stability and rapid clearance of the administered TRAIL protein in circulation have hampered its clinical development…
Read the article →International journal of pharmaceutics2026ResearchNon-viral Gene DeliveryDrug Delivery
Miyazaki T, Kubara K, Kondo K, Kamiyama H, Hara S, Moriya J, Et Al.
mRNA-lipid nanoparticles (LNP) have emerged as a versatile modality, enabling diverse applications by changing encoded mRNA sequences. However, the conventional mRNA-LNP preparation process poses significant barriers to non-specialists because it requires specialized equipment and technical expertise. In this study…
Read the article →Journal of controlled release : official journal of the Controlled Release Society2026ResearchNon-viral Gene DeliveryDrug Delivery
Li P, Abdallah M, Yao Y, Mugan Rs, Payne Tj, Fabb Sa, Et Al.
Lipid nanoparticle (LNP) formulations have enabled the in vivo delivery of messenger ribonucleic acid (mRNA) vaccines and therapeutics yet the delivery of RNA remains relatively inefficient. In order to improve LNP design there is a need to better understand how current mRNA-LNP formulations are trafficked and…
Read the article →Journal of controlled release : official journal of the Controlled Release Society2026ResearchNon-viral Gene DeliveryDrug Delivery
Jacobs W, De Zwaan K, Rutten L, Van Wessel T, Boltje Tj, Cano Lq, Et Al.
Non-viral nanocarriers for oligonucleotide delivery have enormous therapeutic potential, but the factors determining cell type-specific uptake remain incompletely understood. One major cell surface component that delivery vectors encounter is the glycocalyx. While membrane glycans are established interactors for many…
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 →Nature Communications 14, 345 (2023ResearchNon-viral Gene Delivery
Xuexiang Han, Ningqiang Gong, Lulu Xue, Margaret M. Billingsley, Rakan El-Mayta, Sarah J. Shepherd, Mohamad-Gabriel Alameh, Drew Weissman, Michael J. Mitchell
Liver fibrosis has no approved antifibrotic therapies. Activated hepatic stellate cells (HSCs) drive fibrosis by producing collagen, and HSP47 is a key collagen chaperone in these cells. Targeted delivery of siRNA to activated HSCs remains challenging, so a ligand-tethered LNP platform was developed to deliver RNA…
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 →Journal of Controlled Release 344 (2022ResearchNon-viral Gene Delivery
Hamideh Parhiz, Jacob S. Brenner, Priyal N. Patel, Tyler E. Papp, Hamna Shahnawaz, Qin Li, Ruiqi Shi, Marco E. Zamora, Amir Yadegari, Oscar A. Marcos-Contreras, Ambika Natesan, Norbert Pardi, Vladimir V. Shuvaev, Raisa Kiseleva, Jacob W. Myerson, Thomas Uhler, Rachel S. Riley, Xuexiang Han, Michael
Nucleoside-modified mRNA lipid nanoparticle (modmRNA-LNP) technology is clinically successful, but its behaviour in pre-existing inflammatory or immune-challenged conditions is poorly characterised. This gap raises the risk of adverse effects when modmRNA-LNPs are administered to patients with ongoing inflammation…
Read the article →Journal of Controlled Release 341 (2022ResearchNon-viral Gene Delivery
Kelsey L. Swingle, Margaret M. Billingsley, Sourav K. Bose, Brandon White, Rohan Palanki, Apeksha Dave, Savan K. Patel, Ningqiang Gong, Alex G. Hamilton, Mohamad-Gabriel Alameh, Drew Weissman, William H. Peranteau, Michael J. Mitchell
Congenital protein deficiencies often begin irreversible pathology in utero, but postnatal treatments are limited. In utero mRNA delivery could enable protein replacement before disease onset, yet LNP stability in fetal amniotic fluid and how it affects mRNA delivery had not been previously investigated. LNP A12 was…
Read the article →Accounts of Chemical Research2022ResearchNon-viral Gene Delivery
Yulia Eygieris, Mohit Gupta, Jeonghwan Kim, Gaurav Sahay
LNPs enabled the COVID-19 mRNA vaccines and the first siRNA-LNP drug, but there is still no one-size-fits-all LNP for every RNA therapeutic. A better chemistry-level understanding of LNP self-assembly, component roles, and whole-particle properties is needed to rationally design safer and more efficient RNA delivery…
Read the article →Journal of Controlled Release2022ResearchNon-viral Gene Delivery
Martijn J.W. Evers, Wenjuan Du, Qiangbing Yang, Sander A.A. Kooijmans, Aryan Vink, Mies Van Steenbergen, Pieter Vader, Saskia C.A. De Jager, Sabine A. Fuchs, Enrico Mastrobattista, Joost P.G. Sluijter, Zhiyong Lei, Raymond Schiffelers
Modified mRNA (modRNA) is a promising cardiac regeneration therapeutic, but naked mRNA is large, negatively charged, and rapidly degraded. It is unknown whether systemically administered lipid nanoparticles (LNPs) can functionally deliver mRNA to ischaemic/damaged myocardium after myocardial infarction. LNPs were…
Read the article →Journal of Controlled Release 349 (2022ResearchNon-viral Gene Delivery
Annabelle Biscans, Socheata Ly, Nicholas Mchugh, David A. Cooper, Anastasia Khvorova
Lipid-conjugated siRNAs can reach extrahepatic tissues, but silencing efficacy remains lower than in liver largely because only ~1–2% of internalised siRNA escapes endosomes into the cytoplasm. Ionisable lipids enhance endosomal escape in lipid nanoparticles (LNPs), but direct covalent conjugation of an ionisable…
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 →Journal of Biomedical Materials Research Part A2022ResearchNon-viral Gene Delivery
Hanwen Zhang, Xuexiang Han, Mohamad-Gabriel Alameh, Sarah J. Shepherd, Marshall S. Padilla, Lulu Xue, Kamila Butowska, Drew Weissman, Michael J. Mitchell
LNPs can trigger innate immune responses and inflammation, which can suppress mRNA translation and cause adverse effects. There is a need for LNP formulations that reduce LNP-induced inflammation while maintaining or improving mRNA delivery. C9D1 and C10D0 had similar size, PDI, and 90% mRNA encapsulation; Dex…
Read the article →Chemistry and Physics of Lipids 243 (2022ResearchNon-viral Gene Delivery
Yihua Pei, Yanjie Bao, Cristiano Sacchetti, Juthamart Brady, Kyra Gillard, Hailong Yu, Scott Roberts, Kumar Rajappan, Steven P. Tanis, Carlos G. Perez-Garcia, Padmanabh Chivukula, Priya P. Karmali
Systemic LNP delivery predominantly targets the liver, while extrahepatic delivery—especially to lung airway epithelium for diseases such as cystic fibrosis—remains challenging. DOTAP is a common cationic lipid for lung gene delivery but is racemic, pseudo-glyceryl, and slowly biodegradable. Novel readily…
Read the article →Journal of the American Chemical Society (JACS)2021ResearchNon-viral Gene Delivery
Dapeng Zhang, Elena N. Atochina-Vasserman, Devendra S. Maurya, Ning Huang, Qi Xiao, Nathan Ona, Matthew Liu, Hamna Shahnawaz, Houping Ni, Kyunghee Kim, Margaret M. Billingsley, Darrin J. Pochan, Michael J. Mitchell, Drew Weissman, Virgil Percec
Four-component lipid nanoparticles (LNPs) represent the leading non-viral vectors for mRNA delivery, but they have limitations including: (1) segregation of the neutral ionisable lipid as droplets in the LNP core, reducing transfection efficiency to ~1-2%; (2) the "PEG dilemma" where PEGylation increases circulation…
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 →Nano Letters2021ResearchNon-viral Gene Delivery
Sarah J. Shepherd, Claude C. Warzecha, Sagar Yadavali, Rakan El-Mayta, Mohamad-Gabriel Alameh, Lili Wang, Drew Weissman, James M. Wilson, David Issadore, Michael J. Mitchell
Microfluidic mixing can produce precise LNPs but is limited in throughput, while bulk mixing is scalable but yields larger, heterogeneous particles with variable potency. A scalable microfluidic device is needed to produce potent RNA-LNPs across discovery and clinical scales. PMD achieved 18.4 L/h production…
Read the article →2020ResearchNon-viral Gene Delivery
Vitor Francisco, Catarina Rebelo, Artur Filipe Rodrigues, Josephine Blersch, Hugo Fernandes, Lino Ferreira
Non-viral vectors such as nanoparticles (NPs) show promise for RNA-based therapies, but suffer from limited cell targeting, poor cellular internalisation, and inadequate endolysosomal escape capacity. The field lacks a systematic, high-throughput approach to identify effective polymeric nanocarriers that can deliver…
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