NIR-II Photosensitizer-Based Nanoparticles Defunctionalizing Mitochondria to Overcome Tumor Self-Defense by Promoting Heat Shock Protein 40

Inherent self-defense pathways within malignant tumors include the action of heat shock proteins (HSPs) and often impede photothermal therapy efficacy. Interestingly, HSP40 inhibits glycolysis and disrupts mitochondrial function to overcome tumor self-defense mechanisms and exhibits a tumor-suppressive effect. Reactive oxygen species (ROS), especially hydroxyl radicals, generated by type-I photodynamic therapy inhibit adenosine triphosphate (ATP) production and lead to ATP-independent HSP40 overexpression during heat stress. However, the regulatory mechanisms linking heat and hydroxyl radicals to induce HSP40 expression remain unclear. Therefore, it is imperative to elucidate the underlying mechanism governing the induction of HSP40 expression during heat stress and explore its potential as a promising therapeutic strategy against tumor development. By strategically modifying the aza-BODIPY structure to precisely distribute the excited-state energy, we have demonstrated that HSP40 specific expression is correlated with the proportion of heat to hydroxyl radicals rather than their individual levels. This orchestrated NIR-II photosensitizer-based nanoparticles reduced tumor glycolysis and disrupted ATP production, driving cell apoptosis and amplifying the efficacy of photothermal therapy. Silencing and compensation of HSPs under heat and ROS stress represent a promising and effective strategy for overcoming tumor self-defense mechanisms in cancer therapy.