From Molecular Synthesis to Supramolecular Structure: Deciphering the Activity of RNA Lipid Nanoparticles

Marshall S. Padilla, PhD
Postdoctoral Fellow
Department of Bioengineering
University of Pennsylvania
Philadelphia, PA, USA   

This conference is part of the the IRCM Early-Career Scientist Seminar Series (ECS3), a groundbreaking initiative whose mission is to showcase early career scientists. This is a great opportunity to discover the exciting projects of these researchers in training in front of a multidisciplinary audience.

About this conference
Lipid nanoparticles (LNPs) are the leading vehicles for RNA medicines, as seen with the mRNA COVID-19 vaccines. Yet most programs still rely on brute-force screens of hundreds to thousands of formulations because clear structure–activity relationships (SARs) are missing, limiting rational design of next-generation LNPs. 
In my seminar, I will show how my lab bridges chemistry and biophysics to define actionable SARs at both the molecule and particle levels. First, through synthesis of terminally branched ionizable lipids, we discovered architectures that enhance endosomal escape, validated by in vitro and in vivo assays and supported by molecular-dynamics simulations. These designs increased hepatic gene editing with mRNA and RNP cargoes in mice and boosted ex vivo transfection of human primary T cells. 

Second, I will present a high-resolution, solution-based biophysical toolkit, small-angle X-ray scattering, analytical ultracentrifugation, and multi-angle light scattering, to quantify LNP physicochemical properties, internal structure, and shape. By linking these measurements to performance across biological models, we reveal new SARs, including how lipid–RNA interactions govern translation. Together, these results provide data-driven design rules to replace ad hoc screening and accelerate development of clinically relevant LNPs.

About Marshall Padilla
Dr. Marshall Padilla earned his Ph.D. in chemistry from the University of Wisconsin-Madison, where he developed new hydrophobic biomaterials for nanoemulsion-based drug delivery systems. Currently, Dr. Padilla is a Postdoctoral Fellow in the Department of Bioengineering at the University of Pennsylvania, under the mentorship of Professor Mike Mitchell. His research focuses on the structure–function relationships of mRNA lipid nanoparticles, combining the synthesis of novel lipid architectures with advanced biophysical characterization to engineer next-generation therapeutics. As a recipient of an NIDCR T90 fellowship, Dr. Padilla is applying these lipid nanoparticle technologies to develop new interventions for oral cancer therapy.

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