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However, extending RNA delivery beyond the liver to extrahepatic tissues, including the spleen, lungs, lymph nodes, brain, and tumors, remains challenging because of the intrinsic hepatotropism of conventional LNPs and their limited cell\u2010type specificity. Recent advances in lipid chemistry, particle engineering, surface functionalization, protein corona modulation, and route\u2010specific administration have enabled new strategies to redirect LNPs toward specific tissues and cell populations. This review systematically examines these approaches and highlights key determinants of LNP tropism, including formulation composition, surface properties, endogenous protein adsorption, and administration route. We further discuss the clinical translation of extrahepatic LNP delivery, covering clinically validated products, emerging therapeutic candidates, and gaps between preclinical models and human applications. Major challenges include cell\u2010resolved biodistribution, long\u2010term safety, repeated\u2010dose immunogenicity, cross\u2010study comparability, and standardized quantitative assessment. Finally, we explore how high\u2010throughput screening, machine learning, and data\u2010driven design can accelerate the rational optimization of next\u2010generation LNPs. These advances may facilitate precise tissue\u2010 and cell\u2010selective RNA delivery, expanding the therapeutic potential of RNA medicines beyond the liver.<\/jats:p>","DOI":"10.1002\/adma.75408","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:31:39Z","timestamp":1792380699000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Emerging Lipid Nanoparticle Targeting Strategies for Extrahepatic Delivery of RNA Therapeutics"],"prefix":"10.1002","author":[{"given":"Jiaxin","family":"Li","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory for Bioengineering and Sensing Technology School of Chemistry and Biological Engineering University of Science and Technology Beijing  Beijing P. R. 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