A Self-Reinforcing LipoTIDE Nanoplatform That Overcomes Lipid-Buffering Ferroptosis Resistance for Enhanced Cancer Therapy.

Lipid metabolic rewiring is a hallmark of malignancy, allowing tumor cells to sequester fatty acids within lipid droplets (LDs) as a protective reservoir that quenches reactive oxygen species (ROS)-driven lipid peroxidation and thereby evades ferroptosis. Although lipophagy selectively degrades LDs to release free fatty acids (FFAs) and remodel lipid homeostasis, leveraging this process to overcome lipid-buffering ferroptosis resistance remains largely unexplored. Here, we report LipoTIDE (Lipophagy-Tuning Induced Death Enhancer), a self-reinforcing nanoplatform that primes lipophagy-primed ferroptosis by coupling precise lipophagy activation with catalytic ROS generation to dismantle LDs-mediated metabolic defenses in tumors. LipoTIDE co-delivers ultrasmall Pt3Co nanoalloys and tamoxifen within a pH-responsive amphiphilic polymer, enabling tumor-targeted disassembly and localized therapeutic amplification. Triggered by the tumor acidity, LipoTIDE releases Pt3Co nanoalloys for multiple catalytic activities and tamoxifen for initiating lipophagy and decreasing pH value, establishing a self-reinforcing loop that sustains lipophagy and ferroptosis. Additionally, FFAs from lipophagy, together with the Pt3Co nanoalloys, resensitize resistant cancer cells to Pt3Co-catalyzed ROS, thereby amplifying ferroptosis. Consequently, LipoTIDE precisely disrupts lipid homeostasis, triggers robust ferroptotic tumor suppression, and exhibits minimal systemic toxicity. These findings establish lipophagy-primed ferroptosis as a generalizable and actionable strategy for dismantling lipid-buffering defenses of tumors.