Targeting strategies of lipid nanoparticles for RNA therapeutics: From hepatic tropism to extrahepatic precision delivery.

Lipid nanoparticles (LNPs) have revolutionized nucleic acid therapeutics, yet their inherent ApoE-mediated liver tropism remains a formidable barrier to extrahepatic applications. This review critically synthesizes emerging breakthroughs in engineering next-generation LNPs for precision targeting. We first categorize advancements in passive targeting via physicochemical modulation, followed by a rigorous evaluation of active targeting through ligand functionalization (e.g., antibodies, aptamers). Central to this discussion is the ongoing paradigm shift from empirical screening to mechanism-guided design, highlighted by the "Selective Organ Targeting" (SORT) framework, endogenous protein corona programming, and novel ionizable lipid architectures. These strategies have enabled potent delivery to diverse extrahepatic niches, including the lungs, spleen, and tumors. Furthermore, we address persistent translational hurdles, such as the "PEG dilemma" in ligand conjugation and the clinical unpredictability of the protein corona. By integrating AI-driven discovery with multi-strategy synergy, the field is moving toward a future of programmable, cell-specific therapeutics. This review provides a roadmap for navigating the complexities of non-viral vector design in the post-vaccine era.