Mechanistic insights on structure, topology and radiation effects on RNA nanomedicines

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Gaurav  Sahay
Organization: OREGON STATE UNIVERSITY
Fiscal Year: 2024
Award: $530,230
Funding agency: National Cancer Institute

PROJECT ABSTRACT
RNA therapeutics and their corresponding nanomedicines are poised to rapidly change the landscape of
healthcare. To address needs in various diseases, RNA-based technologies must function in vivo with
biological interactions at various levels from whole body (systemic biodistribution and immunological) to
tissues and organs, to intracellular trafficking and endosomal release. Unfortunately in oncology, efficient
systemic delivery of lipid nanoparticles (LNPs) to solid tumors has been plagued by poor tissue
accumulation largely due to a gap in the knowledge of fundamental interactions between these materials
and biological systems. Here we propose to investigate the structure-activity-relationship (SAR) of
nanoparticle carriers through use of a chemically and topologically diverse library of lipopolymers fine-
tuning the biointerface of RNA-LNP. Utilizing a combined barcoding and serial in-depth mechanistic
assays, we will test our central hypothesis that a defined series of first-principles relationships govern the
biophysical interactions of LNPs in vivo. Using cancer models, we will correlate the spatial and temporal
accumulation of mRNA at target tissues and cells with biophysicochemical properties of the LNP
biointerface. The goal of this project is to establish a framework of physiochemical properties to guide the
development of RNA-LNP based cancer nanomedicines. We will achieve this goal by the pursuing the
following aims: Aim 1 - Structural and topological fine-tuning of LNPs biointerface. Aim 2 - Elucidate the
biological interactions of LNPs with respect to whole-body, tissue-level, and intracellular distributions. Aim
3 - Investigate the biological interaction and efficacy of LNPs in the context of multimodal breast cancer
therapy. The immediate outcomes of this research will be applied toward advancing the use of
nanotechnology in oncology. Our project will yield a critical and detailed understanding of the role the LNP
biointerface and its effects on the fate of LNPs in complex biological systems as well as their efficacy. This
invaluable knowledge would greatly aid in future developments in nanomedicine as a whole.

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