2021 Research Conference

Gaurav Sahay, PhD, Associate Professor, Oregon State University

Gaurav Sahay is an Associate Professor in the Department of Pharmaceutical Sciences, College of Pharmacy at Oregon State University. Dr. Sahay’s lab is developing novel nanotechnology-based platforms including lipid-based nanoparticles for effective delivery of messenger RNA therapeutics for treatment of cystic fibrosis, retinal degeneration and against SARS-CoV2. He has done pioneering work to dissect the intracellular transport essential for nucleic acid delivery to the cytosol and developed methods to overcome endosomal barriers.

He has more than 50-peer-reviewed publications in top tier journals including Science Advances, Nature, Nature Communications, Nature Biotechnology, Nature Nanotechnology, Journal of Controlled Release, Nano Letters etc. He is the winner of 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, 2020 Phi Kappa Phi OSU Emerging Scholar Award and 2020 CMBE Young Innovator Award.

He serves as the Principal Investigator on awards funded through the National Institutes of Health, Cystic Fibrosis Foundation, and biotech companies. He serves as a consultant and scientific advisory board member to several biotech and venture capital firms. He was the Chair of the 2018 NanoMedicine and Drug Delivery Symposium (NanoDDS, Portland, OR) and Chair of GDGE Focus Group at CRS (2019-2021). Dr. Sahay completed his postdoctoral research with Prof. Robert Langer and Prof. Daniel Anderson at the Koch Institute for Integrative Cancer Research at MIT and received his Ph.D. from the University of Nebraska Medical Center under the mentorship of Prof. Alexander Kabanov.

Boosting intracellular delivery of mRNA

The field of nanomedicine is moving from an age of renaissance towards industrial revolution. In part due to the transformational impact of lipid nanoparticle (LNP) enabled mRNA vaccines against SARS-CoV2. Our lab has worked extensively onto understanding 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 analogues reveals that incorporation of C-24 alkyl phytosterols into LNPs (eLNPs) causes 200-fold improvement in gene transfection and the length of alkyl tail, flexibility of sterol ring and polarity due to -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. 3D single-particle tracking shows enhanced intracellular diffusivity of eLNPs relative to LNPs, suggesting eLNP traffic to productive pathways for escape. Based on these findings we designed next generation
LNPs for deliver mRNA for gene delivery and editing i.e., for the treatment of cystic fibrosis, retinal degeneration, and COVID-19 therapeutics.

Our 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.