Membrane-inspired lipid nanoparticles for cell-type-specific expression of programmable RNA

/Abstract Precise delivery of biomolecules to specific cell types is essential for elucidating cellular functions and advancing precision molecular therapies. While viral vectors have achieved significant advances in targeted gene delivery through capsid engineering and cell-type-specific promoters, they are limited by immunogenicity, restricted cargo capacity, and scalability challenges. Non-viral lipid nanoparticles (LNPs) offer advantages such as high payload capacity, low immunogenicity, and scalable production. However, achieving the cell-type specificity inherent to viral systems remains a critical challenge. This proposal seeks to advance gene delivery by integrating the scalability and versatility of LNPs with the precise cell-type targeting of viral vectors. We introduce two innovative strategies: (1) Bio-inspired design of LNPs to enhance transfection efficiency and specificity, and (2) Development of programmable RNA sensors that enable cell-type-specific expression of transgenes. We will employ a multidisciplinary approach combining nanotechnology, synthetic biology, and systems neuroscience. We will develop novel LNP formulations and characterize their physicochemical properties and cellular interactions using advanced imaging and biophysical techniques. In parallel, we will design and screen RNA sensors that respond to endogenous cell-specific transcripts, encapsulate them in optimized LNPs, and evaluate their specificity and efficacy both in vitro and in vivo. The development of scalable, precise gene delivery platforms will transform our ability to manipulate and study cellular functions in the central nervous system and peripheral organs, paving the way for next-generation precision therapies. Project Number: 1R35GM162214-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Ritchie Chen | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $445,049 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 MCST-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11270597