A Dual Heat Shock Protein Down‐Regulation Strategy Using PDA/Cu/ICG/R Controlled by NIR “Switch” Enhances Mild‐Photothermal Therapy Effect

Abstract The purpose of this study is to down‐regulate heat shock proteins and improve the mild photothermal therapy (mild‐PTT) effect of polydopamine (PDA) by preparing the nanosystem of Cu2+ and indocyanine green (ICG)–loaded PDA nanospheres with surface modification of integrin‐targeted cyclic peptide (cRGD) (PDA/Cu/ICG/R), which can limit ATP synthesis through the double mitochondrial destruction pathway. In vitro and in vivo experiments using PDA/Cu/ICG/R irradiated with an NIR laser demonstrate that when NIR is “OFF,” Cu2+ can undergo Fenton‐like reaction in tumor cells, producing a large amount of hydroxyl radicals (·OH), which leads to oxidative stress in cells. This oxidative stress can cause mitochondrial oxidative phosphorylation dysfunction, resulting in limited ATP synthesis. When NIR is “ON,” mild‐PTT can accelerate Cu2+ to produce ·OH. Simultaneously, NIR can activate ICG to produce reactive oxygen species (ROS) storm, amplify intracellular oxidative stress, and continuously damage mitochondria. The biodegradability of PDA greatly reduces the risk of toxicity caused by long‐term retention of PDA/Cu/ICG/R in organisms. Finally, the improvement of the mild‐PTT effect of PDA is successfully achieved through the double mitochondrial destruction pathway of Cu2+ and ICG controlled by NIR “switch.”