Near-Infrared-Responsive, Oxygen Self-Sufficient Nanoparticles for Combined Photothermal and Thermally Activated...

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 (ΔT > 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.