H2O2/O2 Self-Supplied Nanoplateform for amplifying oxidative stress to Accelerate Photodynamic/Chemodynamic therapy Cycles

Photodynamic (PDT) and chemodynamic therapies (CDT) relying on reactive oxygen species-mediated treatments mainly face various challenges of hypoxia, endogenous hydrogen peroxide (H 2 O 2 ) deficiency, and glutathione (GSH) overexpression in the tumor microenvironment. Herein, we propose a novel strategy using a core–shell structured nanocomposite, UCNP@mSiO 2 @5-ALA-CaO 2 -Cu(UA@CC). The strategy centers on upconverting NPs and then utilizes mesoporous silica loaded with 5-aminolevulinic acid (5-ALA) to maximize the enrichment of protoporphyrin IX (Pph IX), an intra-tumor photosensitizer. Then in the acidic tumor microenvironment (TME), CaO 2 in the outer layer reacts with H 2 O to form O 2 , H 2 O 2 and Ca 2+ , and the released H 2 O 2 serves as an auxiliary “fuel” to induce acceleration of the Fenton-like (Cu 2+ ) reaction and inactivation of the antioxidant GSH enzyme, thus enhancing the tumor cells’ Catalysis. Furthermore, under the excitation of a 980 nm laser, 5-ALA-mediated PDT and Cu + -based CDT were initiated. Through interconnected processes of Ca 2+ overload, self-supply of H 2 O 2 /O 2 , and enhanced GSH depletion, an accelerated cycling strategy for combined PDT/CDT therapy was established, resulting in amplified oxidative stress and anti-tumor capabilities, which was validated in cancer cells and melanoma mouse models.