ConspectusRNA-based therapeutics are now revolutionizing modern medicine, with examples like COVID-19 mRNA vaccines and the siRNA drug Leqvio, validating their potential in infectious diseases and chronic diseases. However, the broad clinical translation of RNA therapeutics remains critically dependent on the development of safe and effective delivery systems that are capable of overcoming physiological barriers and achieving precise spatiotemporal upregulation or downregulation of target proteins. Lipid nanoparticles (LNPs) have attracted significant attention due to their clinical success, yet they still struggle to overcome context-specific delivery barriers, such as poor stability in blood or gastrointestinal fluids, lack of disease-microenvironment responsiveness, and insufficient cell-type targeting, which hinder the full implementation of RNA therapeutics across a broad spectrum of diseases. To tackle the unmet needs in RNA-based therapeutics, developing new types of delivery platforms with different nanoparticle structures is therefore highly attractive and needed.Over the past decade, our group has focused on developing novel lipid-polymer hybrid nanoparticles (LPHNPs) for the delivery of RNA therapeutics across diverse biomedical applications. By incorporating biodegradable polymers with tailored properties, for example, poly(lactic--glycolic acid) (PLGA) for structural stability, hyaluronic acid (HA) for CD44-mediated targeted delivery, and l-cysteine-based poly(disulfide amide) (Cys-PDSA) for redox-responsive release in the tumor microenvironment, these LPHNPs exhibit highly tunable architectures that integrate efficient RNA encapsulation, site-specific delivery, and controlled RNA release, providing more tools and choices for RNA delivery.In this Account, we summarize recent advances from our group in the design and synthesis of LPHNPs for RNA therapeutics, as well as their translational applications across diverse disease contexts. We highlight rational material pairings and design principles that optimize key performance metrics, including colloidal stability, RNA loading, cellular uptake, endosomal escape, and targeting efficacy. We also provide case studies demonstrating the translational potential of RNA-LPHNPs across various administration routes and disease models, including oral, inhaled, intravenous, and intravesical delivery, using the LPHNP platforms developed in our laboratory. These platforms have achieved promising therapeutic efficacy in models of cancers, inflammatory diseases, and respiratory conditions by enabling local or systemic delivery of mRNA or siRNA to immune cells, epithelial cells, and tumor microenvironments. By outlining optimized design strategies and future challenges, this Account aims to serve as a roadmap for researchers seeking to develop next-generation RNA delivery platforms that are modular, functionally versatile, and translatable. co
