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

ABSTRACT 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 Pt 3 Co nanoalloys and tamoxifen within a pH‐responsive amphiphilic polymer, enabling tumor‐targeted disassembly and localized therapeutic amplification. Triggered by the tumor acidity, LipoTIDE releases Pt 3 Co 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 Pt 3 Co nanoalloys, resensitize resistant cancer cells to Pt 3 Co‐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.