Mrna/lipid nanoparticle-mediated genome editing in the brain

The National Institute of Biomedical Imaging and Bioengineering awarded The Research Foundation For The State University Of New York $244,500 on August 15, 2026, under the Discovery and Applied Research for Technological Innovations to Improve Human Health program (CFDA 93.286) to develop and mechanistically characterize sulfonium-based lipid nanoparticles for mRNA and CRISPR/Cas9 delivery to the brain. The award funds research to elucidate how sulfonium-based lipid nanoparticles mediate transfection in brain tissue and to evaluate their efficacy for gene editing using mRNA and guide RNA cargo, with the goal of providing a framework for safe delivery of gene-editing components across the blood-brain barrier to enable therapeutic strategies for inherited and acquired neurological disorders. Work is performed in Syracuse, New York, with a period of performance from August 15, 2026, through July 31, 2028. The Research Foundation For The State University Of New York, operating as Upstate Medical Center, serves as the sponsored programs administrator and fiscal agent for the State University of New York system, managing federal grants and contracts across distributed SUNY institutions.

Abstract

Gene editing technologies such as crispr/CAS9 hold tremendous promise for correcting disease-causing mutations in the central nervous system (CNS), but safe and efficient delivery of editing components across the blood-brain barrier (BBB) remains a major challenge. Viral vectors like adeno-associated viruses (AAVS) can achieve CNS expression but are limited by immunogenicity, insertional mutagenesis risk, and lack of dosing control. Nonviral lipid nanoparticles (LNPS) offer a safer and more flexible alternative; however, existing LNP formulations show low efficiency and poor biodistribution in the brain. This project aims to develop and mechanistically characterize a new class of sulfonium-based lipid nanoparticles (SLNPS) designed for efficient delivery of mrna and crispr/CAS9 components to brain cells. Preliminary data show that SLNPS mediated mrna delivery achieves markedly higher transfection efficiency than benchmark formulations. In this proposal, we will (1) elucidate the mechanistic basis of slnp-mediated transfection in brain tissue, and (2) evaluate the efficacy of SLNPS for mediating crispr-CAS9 based genome editing using mrna and guide RNA cargo. Successful completion will provide a mechanistic framework and preclinical proof-of- concept for using SLNPS to safely deliver gene-editing component to the brain, enabling new therapeutic strategies for currently untreatable inherited and acquired neurological disorders.