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Despite its clinical success, tamoxifen (TMX) therapy faces challenges, such as drug resistance development; a key resistance mechanism involves intracellular lipid alterations. Lipid droplets (LD) play a crucial role in cancer progression and resistance to therapy. However, the direct suppression of LD formation as a synergistic adjunct to enhance TMX delivery remains underexplored. In this study, a supramolecular micelle platform based on amphiphilic tetraphenylethylene derivatives are presented with tunable oligoethylene glycol (OEG) side\u2010chain lengths. By modulating the OEG length, micelles with distinct surface charges are developed that significantly improve intracellular the TMX delivery to LDs. Furthermore, this system enabled visualization of intracellular drug distribution via intrinsic fluorescence. This targeted delivery reveales that LD\u2010mediated TMX sequestration is a resistance mechanism in estrogen receptor\u2010positive breast cancer. Importantly, co\u2010treatment with orlistat, an LD formation inhibitor, disrupted this resistance pathway and markedly enhance TMX efficacy of TMX. This dual\u2010functional approach, combining organelle\u2010specific delivery and LD modulation, constitutes a powerful supramolecular strategy to overcome TMX resistance and advances the development of next\u2010generation cancer therapeutics.<\/jats:p>","DOI":"10.1002\/adhm.202502060","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T10:40:26Z","timestamp":1755081626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synergistic Combination of Tamoxifen\u2013Tetraphenylethylene Co\u2010Assembled Micelles and Orlistat\u2010Induced Lipid Droplet Inhibition to Overcome Tamoxifen Resistance"],"prefix":"10.1002","volume":"14","author":[{"given":"Jung Yeon","family":"Park","sequence":"first","affiliation":[{"name":"KU\u2010KIST Graduate School of Converging Science and Technology Korea University  Seoul 02841 Republic of 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