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However, conventional LNPs typically consist of multiple lipid components, which complicates formulation optimization and limits compositional flexibility. Furthermore, efficient delivery of siRNA to extrahepatic tissues, including solid tumors, remains a major challenge. To address these limitations, we developed a class of ionizable cholesterol derivatives by conjugating biocompatible dimethylated amino acids to cholesterol through a cleavable linker, thereby integrating the structural role of cholesterol and the pH\u2010responsive ionization of ionizable lipids into a single molecule. Five i\u2010Chol derivatives were synthesized and formulated into LNPs, which demonstrated efficient siRNA encapsulation and delivery in cancer cells. The resulting siRNA@i\u2010Chol LNPs exhibited uniform particle size and near\u2010neutral surface charge, indicating favorable physicochemical properties for systemic administration. Notably, phenylalanine\u2010based cholesterol LNPs (Phe\u2010Chol LNPs) loaded with siRNA targeting kinesin spindle protein (KIF11) achieved the most potent in vitro gene knockdown in PC3 prostate cancer cells and induced significant dose\u2010dependent antitumor activity in a xenograft model without observable systemic toxicity. Collectively, this study establishes a simplified i\u2010Chol LNP platform that maintains high siRNA delivery efficiency to solid tumors and provides a versatile framework for further LNP engineering and scalable manufacturing.<\/jats:p>","DOI":"10.1002\/cmdc.70464","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T03:55:06Z","timestamp":1787716506000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ionizable Cholesterol\u2010Integrated Lipid Nanoparticles for Efficient siRNA Delivery to Solid Tumors"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1175-8413","authenticated-orcid":false,"given":"Suyoung","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Biological Sciences KAIST Institute for the BioCentury Korea Advanced Institute of Science and Technology (KAIST)  Daejeon Republic of Korea"},{"name":"Center for 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