Simultaneous Inhibition of Heat Shock Response and Autophagy with Bimetallic Mesoporous Nanoparticles to Enhance Mild‐Temperature Photothermal Therapy

Mild‐temperature photothermal therapy (MPTT) is a promising tumor therapeutic modality because it can avoid the damage of normal tissues near the tumor caused by excessive heat. However, its therapeutic effect is severely impaired because tumor cells can develop heat resistance and self‐repair by activating heat shock response and cell autophagy. Herein, a tannic acid–iron ion metal organic framework‐coated, chloroquine (CQ)‐loaded mesoporous PdPt nanosystem (TF‐CQ@mPdPt) is developed to enhance MPTT by simultaneous suppression of heat shock response and autophagy. TF‐CQ@mPdPt exhibits good peroxidase (POD)‐mimic activity and photothermal performance. As a result, the reactive oxygen species generated by POD‐mediated decomposition of endogenous hydrogen peroxide damage mitochondria, leading to limitation of adenosine triphosphate supply, which suppresses the upregulation of heat shock proteins of tumor cells during MPTT, making tumor cell more sensitive to heat stress. Concurrently, CQ released from TF‐CQ@mPdPt during MPTT inhibits cell autophagy, thereby interrupting the self‐repair pathway of tumor cells. Consequently, TF‐CQ@mPdPt‐mediated MPTT significantly enhances its therapeutic effect, effectively inhibiting tumor progression in 4T1 tumor‐bearing mice. This study presents a novel strategy to enhance MPTT by simultaneously suppressing heat shock response and autophagy.