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

The National Institute of General Medical Sciences awarded The Regents of the University of California, San Francisco $445,049 on April 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to develop membrane-inspired lipid nanoparticles for cell-type-specific expression of programmable RNA.

The recipient will design novel lipid nanoparticle formulations to achieve precise, scalable delivery of biomolecules to specific cell types, combining bio-inspired engineering with programmable RNA sensors that respond to endogenous cell-specific transcripts. The project integrates nanotechnology, synthetic biology, and systems neuroscience to characterize physicochemical properties and cellular interactions using advanced imaging and biophysical techniques, then evaluate specificity and efficacy in vitro and in vivo. The work targets applications in the central nervous system and peripheral organs to advance precision molecular therapies and cellular function research.

Performance occurs in San Francisco, California from April 1, 2026 through March 31, 2031.

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.