Biomaterials Science (accepted manuscript; manuscript ID BM-ART-09-2020ResearchNon-viral Gene Delivery
Rui Zhang, Rakan El-Mayta, Timothy Murdoch, Claude Warzecha, Margaret Billingsley, Sarah Shepherd, Ningqiang Gong, Lili Wang, James Wilson, Daeyeon Lee, Michael J. Mitchell
LNP delivery to liver versus spleen is difficult to predict from formulation parameters, and the role of helper phospholipids in biodistribution and protein adsorption is incompletely understood. This study probed how helper lipid identity (DOPE vs DSPC) affects LNP accumulation in liver/spleen and interactions with…
Read the article →Acta Biomaterialia2020ResearchNon-viral Gene Delivery
Yusuke Sato, Nana Okabe, Yusuke Note, Kazuki Hashiba, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima
Small-sized lipid nanoparticles (LNPs) are attractive for tissue penetration but often lose potency because lipid components diffuse out and serum proteins adsorb onto poorly packed surfaces. The study asked how the hydrophobic scaffold structure of pH-sensitive cationic lipids affects small-LNP stability, lipid…
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 Controlled Release2020ResearchNon-viral Gene Delivery
Pedro P. Guimaraes, Rui Zhang, Roman Spektor, Mingchee Tan, Amanda Chung, Margaret M. Billingsley, Rakan El-Mayta, Rachel S. Riley, Lili Wang, James M. Wilson, Michael J. Mitchell
LNP libraries are usually screened in vitro, which poorly predicts in vivo mRNA delivery. A high-throughput in vivo platform was needed to screen many LNP formulations simultaneously and identify lead carriers for functional mRNA delivery. b-mRNA could be detected in liver at doses as low as 17 ng; b-mRNA delivery…
Read the article →Journal of Controlled Release2020ResearchNon-viral Gene Delivery
Nour Shobaki, Yusuke Sato, Yuichi Suzuki, Nana Okabe, Hideyoshi Harashima
Tumour-associated macrophages (TAMs) are largely M2-like and promote tumour growth, angiogenesis, metastasis, and immune suppression. There is a need for systemic delivery systems that can target TAMs and manipulate their pro-tumour functions with siRNA for cancer immunotherapy. Optimised CL4H6-LNPs had 90% siRNA…
Read the article →Nature Communications2020ResearchNon-viral Gene Delivery
Siddharth Patel, N. Ashwanikumar, Ema Robinson, Yan Xia, Cosmin Mihai, Joseph P. Griffith Iii, Shangguo Hou, Adam A. Esposito, Tatiana Ketova, Kevin Welsher, John L. Joyal, Örn Almarsson, Gaurav Sahay
Endosomal sequestration of lipid-based nanoparticles (LNPs) remains a formidable barrier to delivery, with only <2% of LNPs reaching the cytosol. The role of cholesterol structure in LNP-mediated mRNA delivery and endosomal escape was poorly understood. There is a need to decode the structural characteristics of…
Read the article →Nanoscale2019ResearchNon-viral Gene Delivery
Dongyu Chen, Neha Parayath, Shanthi Ganesh, Weimin Wang, Mansoor Amiji
The protein corona that forms on lipid nanoparticles (LNPs) after systemic administration can alter their biological identity, but its impact on tumour delivery is not well understood. This study aimed to determine whether LNP formulation composition and surface charge can manipulate the protein corona and thereby…
Read the article →Nanoscale2019ResearchNon-viral Gene Delivery
Dongyu Chen, Shanthi Ganesh, Weimin Wang, Mansoor Amiji
Protein corona formation in biological fluids can alter nanoparticle cellular uptake, transfection, and gene silencing, but the relationship between LNP surface chemistry and corona-mediated delivery is incompletely understood. This study examined how PEG lipid chain length and PEG molar ratio affect protein corona…
Read the article →Journal of Controlled Release2019ResearchNon-viral Gene Delivery
Yusuke Sato, Kazuki Hashiba, Kosuke Sasaki, Masatoshi Maeki, Manabu Tokeshi, Hideyoshi Harashima
Endosomal escape remains a major rate-limiting step for siRNA delivery. The structure–activity relationships (SAR) of pH-sensitive cationic lipids were incompletely understood, limiting rational design of lipid nanoparticles (LNPs) for efficient in vivo siRNA delivery to hepatocytes. Hydrophilic head group structure…
Read the article →Nano Letters2019ResearchNon-viral Gene Delivery
Yuhang Jiang, Qiao Lu, Yongheng Wang, Emily Xu, Alison Ho, Priya Singh, Yifei Wang, Zhaozhong Jiang, Fan Yang, Gregory T. Tietjen, Peter Cresswell, W. Mark Saltzman
Endosomal escape is a key but poorly quantified step for intracellular nucleic acid delivery. Existing methods are low-throughput, indirect, or fail to distinguish endosomal disruption from actual cytosolic cargo delivery. A reliable, sensitive method is needed to rationally optimise polymeric mRNA delivery vehicles…
Read the article →Proceedings of the National Academy of Sciences (PNAS)2018ResearchNon-viral Gene Delivery
Ole A. W. Haabeth, Timothy R. Blake, Colin J. Mckinlay, Robert M. Waymouth, Paul A. Wender, Ronald Levy
mRNA-based cancer vaccination is a promising approach for personalised immunotherapy, but safe and effective mRNA delivery remains a major challenge due to mRNA's instability and poor cell membrane permeability. While lipid nanoparticles (LNPs) are the primary delivery strategy, they have limitations with respect to…
Read the article →PNAS2018ResearchNon-viral Gene Delivery
Colin J. Mckinlay, Nancy L. Benner, Ole A. Haabeth, Robert M. Waymouth, Paul A. Wender
Efficient mRNA delivery to lymphocytes remains a major unmet need for immunotherapy and vaccinology. Current methods rely largely on physical transfection such as electroporation, which is ex vivo, costly, and inefficient; chemical vectors generally achieve low lymphocyte mRNA transfection, especially in vivo. Lead…
Read the article →2017ResearchNon-viral Gene Delivery
Petra Furedi, Zsofia Edit Papay, Kristof Kovacs, Borbala Dalmadi Kiss, Krisztina Ludanyi, Istvan Antal, Imre Klebovich
Topical fungal infections, including ocular mycoses, are increasing, and voriconazole (VCZ) is an effective antifungal but has poor water solubility, limiting liquid ophthalmic formulations. Lipid-based nanoparticles (LNPs/SLNs) may improve VCZ solubility, loading, and topical delivery. Optimised formulation (SLN2)…
Read the article →Journal of Biomedical Nanotechnology2016ResearchNon-viral Gene Delivery
Stephen L. Hayward, David M. Francis, Parviz Kholmatov, Srivatsan Kidambi
miRNA-based therapeutics are limited by instability, poor cellular uptake, lack of targeting, and potential immune activation. No nonviral miRNA delivery strategy had been explored as a standalone treatment for HER2-positive metastatic breast cancer. HA-LNP uptake was significantly higher than naked FITC-dextran and…
Read the article →Drug Delivery2016ResearchDrug Delivery
Jie Qu, Liangqiao Zhang, Zhihua Chen, Guohua Mao, Ziyun Gao, Xianliang Lai, Xingen Zhu, Jianming Zhu
Glioblastoma multiforme (GBM) has a poor prognosis due to limited drug delivery across the blood–brain barrier (BBB), therapeutic resistance, and recurrence. Nanocarriers may improve temozolomide (TMZ) delivery, but it is unclear which nanocarrier type—polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs)…
Read the article →Journal of Controlled Release 200 (2015ResearchNon-viral Gene Delivery
H. Akita Et Al.
Cationic gene carriers can mediate cellular uptake but often show poor post-nuclear transcription/translation, toxicity, and aggregation in blood. The study aimed to develop a systemically applicable, tumour-targeting gene carrier that is neutral in blood/cytosol but becomes cationic in endosomes for endosomal…
Read the article →2014ResearchDrug Delivery
Lopes Rm, Gaspar Mm, Pereira J, Eleuterio Cv, Carvalho M, Almeida Aj, Cruz Mem
Current leishmaniasis chemotherapy lacks options that combine high activity, low toxicity, and affordable cost. Oryzalin (ORZ), a dinitroaniline with in vitro antileishmanial activity, is limited by poor water solubility and low accumulation in diseased organs. Lipid-based nanocarriers may overcome these limitations…
Read the article →Molecular Therapy2001ResearchNon-viral Gene Delivery
Adi Mesika, Irina Grigoreva, Muriel Zohar, Ziv Reich
Transfection efficiency of nonviral gene delivery systems remains unacceptably low, largely due to the inability of plasmid DNA to effectively translocate through the nuclear pore complexes (NPCs). While substantial progress has been made in transcriptionally regulated vectors, control over nuclear targeting is…
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