Smart perylenediimide based nanozyme for hypoxia-targeted photodynamic/chemodynamic therapy of skin cancer.

Photodynamic therapy (PDT) for skin cancer is compromised by tumor hypoxia and the limited efficacy of monomodal therapy. Herein, a smart perylenediimide nanozyme MnMSN-NH₂@TAIPDI-BSA is engineered by integrating a highly fluorescent, water-soluble perylenediimide (TAIPDI) derivative with Mn²⁺-mediated Fenton-like catalytic activity into bovine serum albumin functionalized mesoporous silica framework. The π-conjugated TAIPDI chromophore endows the nanohybrid with strong, traceable fluorescence, while nanoscale confinement and Mn2 + -mediated self-oxygenation collectively enhance PDT in an oxygen-independent manner and activate complementary chemodynamic therapy. The nanozyme exhibits tumor microenvironment responsiveness (acidic pH, elevated glutathione), enabling controlled biodegradation of the Mn2+-silica framework and stimuli-triggered TAIPDI release, as confirmed by detailed kinetic studies. Under 530 nm irradiation, the nanozyme exhibited potent in vitro cytotoxicity toward epidermoid carcinoma (A431, IC₅₀ = 13.38 ± 4.58 µg/mL) and melanoma (A375, IC₅₀ = 12.32 ± 3.16 µg/mL) cells under normoxia, with further improvement under hypoxia (IC₅₀ = 11.12 ± 6.96 µg/mL in A431; 7.72 ± 2.89 µg/mL in A375). These findings highlight the potential of biodegradable MnMSN-NH₂@TAIPDI-BSA as a traceable robust self-oxygenating and tumor microenvironment responsive platform for overcoming current limitations associated with PDT and for advancing multimodal onco-theranostics.