Molecularly engineering a lipid nanoregulator destroying the last defense of ferroptosis in breast cancer therapy

Ferroptosis, as a uniquely regulated form of cell death, has garnered significant interest in the field of oncology. Most ferroptosis inducers facilitate the intracellular buildup of lipid peroxidation by inhibiting glutathione peroxidase 4 (GPX4). However, the high saturation level of membrane lipids can shield cancer cells from reactive oxygen species-induced damage, preventing lipid peroxidation triggered by GPX4 inhibitors. Herein, we precisely constructed a lipid nanoregulator of RSL3 and Orlistat through a molecular engineering strategy. In this nanosystem, Orlistat functions as a "dual enhancer", significantly enhancing both the assembly capability and the anti-tumor effectiveness of RSL3. Orlistat can significantly enhance the synthesis of polyunsaturated fatty acids and reduce the saturation level of lipid membranes by inhibiting fatty acid synthase (FASN). Consequently, Orlistat successfully dismantles the final defense (lipid membrane protection), synergistically amplifying ferroptosis with RSL3-induced GPX4 depletion. As expected, the lipid nanoregulator demonstrates a potent antitumor activity in 4T1 tumor-bearing mice. This study represents an effective paradigm for ferroptosis-driven antitumor nanotherapeutics.