A Dual Heat Shock Protein Down-Regulation Strategy using PDA/Cu/ICG/R Controlled by NIR "Switch" Enhances Mild-Photothermal Therapy Effect.

The purpose of this study w as to down-regulate heat shock proteins (HSPs) and improve the mild photothermal therapy (mild-PTT) effect of polydopamine (PDA) by preparing the nanosystem of Cu 2+ and indocyanine green (ICG) loaded PDA nanosphere 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 a NIR laser demonstrated that when NIR is "OFF", Cu 2+ 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 Cu 2+ 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 w as successfully achieved through the double mitochondrial destruction pathway of Cu 2+ and ICG controlled by NIR "switch". This article is protected by copyright. All rights reserved.