The next generation of lipid nanoparticles for in vivo engineering and targeted delivery

The widespread utilization of messenger RNA (mRNA) vaccines has validated lipid nanoparticles (LNPs) as a clinically relevant platform for nucleic acid delivery. However, their broader applicability is presently limited by a "liver bottleneck", wherein more than 90% of systemically administered particles are sequestered within hepatocytes. Advancements in precise in vivo cellular engineering represent the next major challenge, and progress in circumventing hepatic clearance has gained momentum in the treatment of extrahepatic disorders. Numerous next-generation LNPs have been developed, consisting of distinct active components, including biodegradable ionizable lipids, antibody conjugates, and covalent lipids, and employing various targeting strategies such as selective organ targeting, stiffness modulation, and nebulization. In this review, we present a comprehensive overview of these emerging LNP technologies, emphasizing their chemical design and capacity to deliver genetic payloads to targeted tissues. We outline the physiological barriers, such as the blood-brain barrier (BBB) and mucosal surfaces, to elucidate the fundamental principles guiding the design of LNPs for systemic gene editing and immune modulation. We also underscore the benefits and drawbacks of various therapeutic approaches, including ribonucleoprotein (RNP) delivery, in vivo chimeric antigen receptor T (CAR-T) cell production, and mRNA-based protein replacement. The primary challenges concerning immunogenicity and manufacturing scalability, as well as prospective directions involving emerging design approaches, are discussed.