Assembled Gold Superstructure Triggered Synergistic Apoptosis/Ferroptosis via Combined Photo-Enzyme Therapy

Traditional chemotherapy agents often face multiple drug resistance mechanisms in breast cancer and are associated with significant side effects. Innovative phototherapy and enzyme therapy demonstrate potential in ameliorating hypoxic conditions in the tumor microenvironment while inducing oxidative stress. Here, we designed a NIR-triggered multifunctional nanoplatform for the synergistic combination of phototherapy and enzyme therapy in tumors. It encapsulates Au-Au@PEG nanocomponents and integrates gold nanoparticles (AuNPs) and gold nanoclusters (AuNCs) coated with polydopamine (PDA), followed by doxorubicin (DOX) loading. We refer to this formulation as DOX-PDA@Au-Au@PEG (DOX-PAAP). DOX-PAAP is capable of releasing drugs through degradation of the coating under low pH and high glutathione (GSH) conditions. The synergistic effect between the PDA coating and AuNPs significantly enhances the photothermal effect associated with NIR light absorption, thereby improving the therapeutic efficacy. Meanwhile, AuNCs can not only catalyze the decomposition of H 2 O 2 to generate hydroxyl radicals in conjunction with the PDA coating but also produce singlet oxygen under NIR irradiation. This mechanism disrupts the GSH antioxidant axis, thereby promoting the accumulation of lipid peroxidation products (LPO), culminating in dual apoptosis–ferroptosis pathway activation. This study highlights the critical role of NIR phototherapy and enzyme therapy in combination therapies for ferroptosis and apoptosis therapy targeting tumors.