Precision Medicine and Rational Vaccinology Through Spherical Nucleic Acids

Boosting Lipid Nanoparticle-Enabled Intracellular Delivery of mRNA Therapeutics

The field of nanomedicine is moving from an age of renaissance toward industrial revolution due, in part, to the transformational impact of lipid nanoparticle (LNP)-enabled mRNA vaccines against SARS-CoV-2. The Sahay Lab at Oregon State University has worked extensively to understand LNP design, structure, and its impact on intracellular delivery of mRNA. Endosomal sequestration of LNPs remains a formidable barrier to intracellular delivery. Structure-activity analysis of cholesterol analogs reveals that incorporation of C-24 alkyl phytosterols into LNPs (eLNPs) causes a 200-fold improvement in gene transfection. The length of the alkyl tail, flexibility of the sterol ring, and polarity due to the -OH group is required to maintain high transfection. Cryo-TEM displays a polyhedral shape for eLNPs compared to spherical LNPs, while x-ray scattering shows little disparity in internal structure. eLNPs exhibit higher cellular uptake and retention, potentially leading to a steady release from the endosomes over time. Three-dimensional single-particle tracking shows enhanced intracellular diffusivity of eLNPs relative to LNPs, suggesting eLNP traffic to productive pathways for escape.

Based on these findings, the lab designed next-generation LNPs to deliver mRNA for extrahepatic gene delivery and editing for the potential treatment of cystic fibrosis, retinal degeneration, and COVID-19 therapeutics. Their findings emphasize the need for greater insights into surface topology and structural properties of nanoparticles and their subcellular interactions. Next-generation LNPs that enable tissue and cell-type specific delivery of genes and genome editors can revolutionize modern medicine


Speaker

Gaurav Sahay, PhD
Associate Professor, Department of Pharmaceutical Sciences
Oregon State University

Gaurav Sahay is an associate professor in the department of pharmaceutical sciences at the College of Pharmacy at Oregon State University. Sahay’s lab is developing novel nanotechnology-based platforms, including lipid-based nanoparticles for effective delivery of messenger RNA therapeutics for the treatment of cystic fibrosis, retinal degeneration, and against SARS-CoV-2. He has worked to dissect the intracellular transport essential for nucleic acid delivery to the cytosol and developed methods to overcome endosomal barriers. Sahay has 50 peer-reviewed publications in journals including Science Advances, Nature, Nature Communications, Nature Biotechnology, Nature Nanotechnology, Journal of Controlled Release, Nano Letters, and others. He won a 2013 American Association of Pharmaceutical Scientists (AAPS) Postdoctoral Fellow Award, the 2015 Controlled Release Society (CRS) T. Nagai Award, a 2016 American Association of Colleges of Pharmacy (AACP) New Investigator Award, a 2019 Oregon Health & Sciences University (OHSU) Distinguished Faculty Senate Award for Collaboration, a 2020 Phi Kappa Phi OSU Emerging Scholar Award, and a 2020 CMBE Young Innovator Award. The Sahay Lab is funded through the NHLBI, NEI, Cystic Fibrosis Foundation, and several biotech companies. Sahay serves as a consultant and scientific advisory board member to several biotech and venture capital firms. Sahay completed his postdoctoral research with Robert Langer and Daniel Anderson at the Koch Institute for Integrative Cancer Research at MIT and received his doctorate from the University of Nebraska Medical Center under the mentorship of Alexander Kabanov.

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