Photodynamic therapy (
PDT) has emerged as a highly efficacious therapeutic modality for malignant
tumors owing to its non-invasive property and minimal adverse effects. However, the pervasive hypoxic microenvironment within
tumors significantly compromises the efficacy of
oxygen-dependent
PDT, posing a formidable challenge to the advancement of high-efficiency
PDT. Here, we developed a nanostructured
photosensitizer (PS) assembled by cationic and anionic
zinc phthalocyanines to load
oxygen-throttling drug
atovaquone (ATO), which was subsequently coated with
polydopamine to obtain the final product ATO/ZnPc-CA@DA. ATO/ZnPc-CA@DA exhibited excellent stability, particularly in the blood milieu. Interestingly, the acidic microenvironment can trigger drug release from ATO/ZnPc-CA@DA, leading to a significant enhancement in fluorescence and an augmented generation of
reactive oxygen species (ROS). ATO/ZnPc-CA@DA can induce synergistic cytotoxicity of PS and ATO, and significantly enhance the killing ability against
tumor cells under hypoxic conditions. The mechanism underlying cytotoxicity of ATO/ZnPc-CA@DA was demonstrated to be associated with augmented cell apoptosis, disruption of mitochondrial membrane potential, diminished
ATP production, heightened intracellular ROS generation, and reduced intracellular oxygen consumption. The animal experiments indicated that ATO/ZnPc-CA@DA possessed enhanced
tumor targeting capability, along with a reduction in PS distribution within normal organs. Furthermore, ATO/ZnPc-CA@DA exhibited enhanced inhibitory effect on
tumor growth and caused aggravated damage to
tumor tissue. The construction strategy of nanostructured PS and the synergistic antitumor principle of combined
oxygen-throttling drugs can be applied to other PSs, thereby advancing the development of photodynamic antitumor
therapy and promoting the clinical translation.