Signal Transduction and Targeted Therapy2022ReviewNon-viral Gene Delivery
Qin S, Tang X, Chen Y, Et Al.
mRNA therapeutics have fuelled hope to combat incurable diseases, but insufficient understanding of mRNA instability, immunogenicity, and delivery has impeded progress. The review argues that mRNA-based drugs—especially after the COVID-19 vaccine success—can become powerful, versatile tools, and that mRNA…
Read the article →2022ReviewNon-viral Gene Delivery
Chuang St, Conklin B, Stein Jb, Pan G, Lee K-B.
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…
Read the article →Materials Today Advances2022ReviewNon-viral Gene Delivery
Randall A. Meyer, Sarah Y. Neshat, Jordan J. Green, Jose Luis Santos, And Anthony D. Tuesca
mRNA gene therapy has broad therapeutic potential (protein replacement, vaccines, regenerative medicine, oncology), but clinical translation is limited by inadequate understanding of how to target specific organs or cell types for protein expression. Reports on material properties and administration routes are…
Read the article →European Journal of Medicinal Chemistry2022ReviewNon-viral Gene Delivery
Mingyuan Li, Yuan Li, Shiqin Li, Lin Jia, Haomeng Wang, Meng Li, Jie Deng, Ali Zhu, Liqiao Ma, Weihong Li, Peng Yu, And Tao Zhu
The COVID-19 pandemic has greatly accelerated the application of mRNA technology, demonstrating its unique advantages over traditional biopharmaceutical and vaccine technology. However, mRNA instability in human physiological environments and inefficient in vivo delivery remain major barriers. mRNA chemical…
Read the article →Advanced Healthcare Materials2022ReviewNon-viral Gene Delivery
Erin W. Kavanagh And Jordan J. Green
Viral vectors dominate gene therapy but suffer from immunogenicity, insertional mutagenesis risk, cargo-size limits, and manufacturing challenges. Non-viral nanoparticles are safer, more economical, and easier to scale, but their clinical translation has been limited by inefficient delivery, especially for DNA and…
Read the article →Heart Failure Reviews (Springer)2022ReviewNon-viral Gene Delivery
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…
Read the article →Molecules2022ReviewNon-viral Gene Delivery
Wang H-L, Wang Z-G, Liu S-L
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…
Read the article →2022ReviewNon-viral Gene Delivery
Maeki M, Uno S, Niwa A, Okada Y, Tokeshi M
RNA-loaded lipid nanoparticles (LNPs) are clinically validated for siRNA and mRNA delivery, but their therapeutic performance depends critically on reproducible control of size, size distribution, zeta potential, and RNA encapsulation efficiency. Microfluidic devices offer precise mixing, rapid ethanol dilution, high…
Read the article →Journal of Pharmaceutical Investigation.2022ReviewNon-viral Gene Delivery
Karmacharya P, Patil Br, Kim Jo
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…
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…
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…
Read the article →Trends in Biotechnology* (as indicated in the article’s Key Figure footer)2021ReviewNon-viral Gene Delivery
Qurrat Ul Ain, Estefania V.R. Campos, Ariel Huynh, Dominik Witzigmann, Sarah Hedtrich
Gene therapies are powerful tools to prevent, treat, and cure human diseases, but their application to skin diseases has received little attention despite the easy accessibility of skin and urgent medical need. The main obstacle is the unique barrier properties of human skin, which severely limit absorption of…
Read the article →ACS Nano2021ReviewDrug Delivery
Paula M. Cevaal, Abdalla Ali, Ewa Czuba-Wojnilowicz, Jori Symons, Sharon R. Lewin, Christina Cortez-Jugo, Frank Caruso
T cells are attractive targets for immunotherapy, cancer, HIV, autoimmunity, and inflammation, but nanoparticle delivery to T cells remains a major technological challenge due to their nonphagocytic nature and multiple physiological barriers. There is a need for rational design principles for in vivo T cell-targeting…
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 →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 →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 →Biomaterials2021ReviewDrug Delivery
Shepherd Sj, Issadore D, Mitchell Mj.
Nanomedicine translation is limited by non-scalable, batch-variable bulk NP formulation methods that often produce large, polydisperse particles. Microfluidics offers precise control over microscale mixing and nanoprecipitation, enabling more reproducible NPs with controlled size, size distribution, and loading. This…
Read the article →Nature Reviews Drug Discovery2021ReviewNon-viral Gene Delivery
Chaudhary N, Weissman D, Whitehead Ka.
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 optimising mRNA design, intracellular delivery, and applications beyond SARS-CoV-2 prophylaxis. This review describes mRNA vaccine…
Read the article →Frontiers in Immunology2021ReviewNon-viral Gene Delivery
Balakrishnan Pb, Sweeney Ee.
Adoptive T cell therapy has revolutionized treatment of some hematologic malignancies but remains limited in solid tumours—especially central nervous system (CNS) tumours—by poor intratumoral delivery across anatomical barriers, suboptimal T cell specificity or activation, and intratumoral T cell dysfunction caused…
Read the article →Advanced Drug Delivery Reviews2021ReviewNon-viral Gene Delivery
Kim J, Eygeris Y, Gupta M, Sahay G.
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 customisable properties. The review discusses…
Read the article →Nature Communications2021ReviewNon-viral Gene Delivery
Han X, Zhang H, Butowska K, Swingle Kl, Alameh M-G, Weissman D, Mitchell Mj
RNA therapeutics—ASOs, siRNAs, miRNAs, mRNAs, and CRISPR-Cas9 sgRNAs—are limited by nuclease degradation, large size, and negative charge. Ionisable lipids are the key LNP component that condenses RNA, enables endosomal escape, and reduces toxicity. Since 2008, many ionisable lipids have been created, but the field…
Read the article →Bioengineering & Translational Medicine2021ReviewNon-viral Gene Delivery
Schlich M, Palomba R, Costabile G, Mizrahy S, Pannuzzo M, Peer D, Decuzzi P
Endosomal escape remains the major intracellular barrier for RNA therapeutics. Only a small fraction of RNA delivered by ionisable lipid nanoparticles (LNPs) reaches the cytosol, where siRNA, miRNA, mRNA, and CRISPR components must act. A deeper mechanistic understanding is needed to design next-generation LNPs with…
Read the article →Trends in Molecular Medicine2021ReviewNon-viral Gene Delivery
Likely Citation: Swingle Kl, Hamilton Ag, Mitchell Mj
mRNA is degraded by nucleases and cannot easily cross cell membranes because of its large size and negative charge. Delivery therefore requires encapsulation in vehicles such as lipid nanoparticles (LNPs) to enable protein replacement, vaccines, and gene-editing applications. Onpattro was the first FDA-approved…
Read the article →Nature Reviews Materials2021ReviewNon-viral Gene Delivery
Hou X, Zaks T, Langer R, Dong Y
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…
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