Near-Infrared-Responsive, Oxygen Self-Sufficient Nanoparticles for Combined Photothermal and Thermally Activated Photodynamic Therapy in Oxygen-Deficient Environments

Hypoxia severely limits the efficacy of photodynamic therapy (PDT) because oxygen shortage suppresses the generation of cytotoxic reactive oxygen species (ROS). Here we report near-infrared (NIR)-responsive, oxygen self-sufficient nanoparticles (TANPs) that integrate photothermal therapy (PTT) with thermally activated, oxygen self-sufficient PDT and are designed to enhance phototherapy performance in oxygen-deficient settings. TANPs were obtained by nanoprecipitation of an A-D-A type photothermal agent (3TT-IC-4Cl) and a thermally activatable endoperoxide (APO) in DSPE-PEG₂₀₀₀. The nanoparticles showed a uniform spherical morphology with an average hydrodynamic diameter of ∼150 nm, strong NIR absorption, and excellent colloidal and photothermal stability. Upon 880 nm irradiation, TANPs generated robust hyperthermia (Δ<i>T</i> > 50 °C at 180 μg/mL) with a photothermal conversion efficiency of 30.96% and simultaneously produced ROS via thermally triggered APO activation. In vitro, TANPs exhibited negligible dark cytotoxicity but marked light-induced cytotoxicity toward HeLa and 293 cells, outperforming single-mode control nanoparticles (TNPs or ANPs). Flow cytometry confirmed that TANPs induced pronounced early and late apoptosis as a result of combined hyperthermia and ROS-mediated damage. These findings suggest that TANPs constitute a promising nanoplatform to boost phototherapeutic efficacy in oxygen-deficient tumor microenvironments.