Atom engineering for optimized photosensitizer performance in glioma photothermal and photodynamic therapy

Current design strategies for photosensitizers (PSs) remain largely focused on terminal group or alkyl chain modifications, whereas modifications to the molecular skeleton have been scarcely investigated, particularly those involving selenium functionalization. Herein, we developed photosensitizers (RP-S and RP-Se) through atom-engineering modifications incorporating sulfur or selenium into molecular skeletons. Corresponding nanoparticles (RP-S NPs and RP-Se NPs) were also prepared for synergistic phototherapy. Both RP-Se and RP-Se NPs exhibited a significant red-shift in their maximum absorption and emission wavelengths, with an enhanced molar extinction coefficient (ε= 3.01 × 10⁵ M⁻¹cm⁻¹) and a high photothermal conversion efficiency (PCE= 63.76 %). Under 808 nm irradiation, RP-Se NPs exhibited capabilities for fluorescence imaging (FLI) and dual type I/II reactive oxygen species (ROS) production, producing 1.6-fold more total ROS than RP-S NPs. In vitro, RP-Se NPs showed negligible cytotoxicity toward normal cells but achieved nearly 100 % tumor cell ablation upon laser exposure, even in hypoxic conditions. In vivo, a single dose of RP-Se NPs plus 808 nm irradiation effectively suppressed GL261 tumor growth via mitochondrial dysfunction induction, while exhibiting exceptional biocompatibility. This study establishes atom-engineered selenium-modification of the molecular skeleton as a promising strategy for developing high-performance NIR-II phototheranostic agents.