Tumor-Targeting CaO₂-Based Nanoparticles for Cancer Therapy

Photodynamic therapy (PDT) has emerged as a promising noninvasive modality for cancer treatment. However, its therapeutic efficacy is often compromised by the inadequate oxygen supply and overexpressed glutathione (GSH) in the tumor microenvironment (TME). Herein, a multifunctional core–shell nanocomposite CaLI@Z-FA was constructed for targeted and enhanced photodynamic/photothermal synergistic therapy against hypoxic tumors. The integration of l-Arg addresses the limitation of reactive oxygen species (ROS) singularity in traditional PDT by generating nitric oxide (NO), which synergistically enhances the therapeutic efficacy. Folic acid (FA) modification on the nanocomposite surface significantly improves tumor targeting, enhancing the accumulation of nanoparticles at the tumor site. Upon reaching the acidic TME, the ZIF-8 shell decomposed to release CaO2, which generated O2 in situ to relieve tumor hypoxia and enhance the PDT efficacy of ICG under near-infrared irradiation. Meanwhile, the PDT-induced singlet oxygen (1O2) catalyzed l-Arginine to release nitric oxide, which sensitized PDT by depleting intracellular GSH and reacted with 1O2 to generate highly antitumor reactive nitrogen species. Moreover, the photothermal effect of ICG and calcium overload-mediated cell death further potentiated the antitumor efficacy. Both in vitro and in vivo studies demonstrated the tumor-targeting property, enhanced oxidative damage, and outstanding synergistic therapeutic outcomes of CaLl@Z-FA with negligible systemic toxicity. This O2-generating and GSH-depleted nanoplatform provides an effective paradigm for targeted and enhanced cancer phototherapy.