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As obesity and metabolic syndrome rise, MASLD has become a global concern, spurring research into effective treatments. Here, the design of a Lipid droplet inhibitor (LDI) is presented, incorporating porous silica nanostructures along with PKC\u03b1 C1A and Candida Rugosa lipase, aimed at directly degrading lipid droplets. Through its dual\u2010functional design, this nanostructure captures diacylglycerol using PKC\u03b1 C1A while hydrolyzing triacylglycerol into smaller molecular fragments via the lipase. Notably, the amphiphilic biomolecules in LDI facilitate the formation of a Pickering emulsion, ensuring stable localization at the lipid\u2010water interface for efficient interaction with lipid droplets. LDI reduces lipid droplet formation and triglyceride levels in palmitic acid\u2010treated HepG2 cells. In a high\u2010fat diet\u2010induced MASLD model, it alleviateds liver pathology and, lowered injury scores by up to 84%. Furthermore, lipidomic analysis confirmed that LDI effectively modulated the hepatic lipid profile, suggesting its potential as a nanoplatform for counteracting lipid droplet accumulation.<\/jats:p>","DOI":"10.1002\/adma.202506373","type":"journal-article","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T10:50:52Z","timestamp":1759575052000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["LDI, A Lipid Droplet Inhibitor, Disrupts Lipid Accumulation and Modulates Hepatic Lipid Profiles in Fatty Liver"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3745-8385","authenticated-orcid":false,"given":"Seunghee","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Chemistry Hanyang University  Seoul 04763 Republic of Korea"},{"name":"Research Institute for Convergence of Basic Sciences Hanyang University  Seoul 04763 Republic of Korea"},{"name":"VN Inc.  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Seoul 04763 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8074-3823","authenticated-orcid":false,"given":"Jeesoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Advanced Biomolecular Recognition Korea Institute of Science and Technology  Seoul 02792 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunmi","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, Graduate School of Biomedical Science and Engineering Hanyang University  Seoul 04763 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8769-2879","authenticated-orcid":false,"given":"Seung\u2010Hoi","family":"Koo","sequence":"additional","affiliation":[{"name":"Division of Life Sciences, College of Life Sciences and Biotechnology Korea University  Seoul 02841 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Sung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology Hanyang University School of Medicine  Seoul 04763 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2875-6139","authenticated-orcid":false,"given":"Dae Won","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Hanyang University College of Medicine  Seoul 04763 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3835-1837","authenticated-orcid":false,"given":"Jinyoung","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Advanced Biomolecular Recognition Korea Institute of Science and Technology  Seoul 02792 Republic of Korea"},{"name":"Division of Bio\u2010Medical Science and Technology, KIST\u2010School University of Science and Technology  Seoul 02792 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6954-7520","authenticated-orcid":false,"given":"Hyunbeom","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Advanced Biomolecular Recognition Korea Institute of Science and Technology  Seoul 02792 Republic of Korea"},{"name":"Department of HY\u2010KIST Bio\u2010convergence Hanyang University  Seoul 04763 Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9551-6402","authenticated-orcid":false,"given":"Joonseok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Hanyang University  Seoul 04763 Republic of Korea"},{"name":"Research Institute for Convergence of Basic Sciences Hanyang University  Seoul 04763 Republic of Korea"},{"name":"VN Inc.  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