Synergistic Combination of Tamoxifen-Tetraphenylethylene Co-Assembled Micelles and Orlistat-Induced Lipid Droplet Inhibition to Overcome Tamoxifen Resistance.

Nanostructured supramolecular materials enable the precise control of biological interactions by tuning structural features such as size, shape, and surface charge, allowing targeted cellular uptake, optimized biodistribution, and enhance therapeutic efficacy. 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-chain 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-mediated TMX sequestration is a resistance mechanism in estrogen receptor-positive breast cancer. Importantly, co-treatment with orlistat, an LD formation inhibitor, disrupted this resistance pathway and markedly enhance TMX efficacy of TMX. This dual-functional approach, combining organelle-specific delivery and LD modulation, constitutes a powerful supramolecular strategy to overcome TMX resistance and advances the development of next-generation cancer therapeutics.