Self-supplying hydrogen peroxide-driven gold nanoparticle aggregation via bio-orthogonal click reaction activates...

We developed an effective nanoplatform, _T+EPAuNP_Lu&Lap, that concurrently harnesses Type I photodynamic therapy (PDT), chemodynamic therapy (CDT), photothermal therapy (PTT), and immunomodulation to remodel the immunosuppressive tumor microenvironment (TME). By pairing PpIX and EGCG, the system enables the transformation of PpIX from Type II PDT to oxygen-independent Type I for superoxide (O₂•^-) generation, courtesy of electron-richness and low reduction potential of EGCG. Mn²⁺-mediated Fenton-like reaction produces hydroxyl radicals (•OH) for CDT, while its superoxide dismutase (SOD) activity alleviates tumor hypoxia. β-Lapachone-triggered H₂O₂ elevation augments luminol chemiluminescence, which not merely fortifies CDT, but also induces bio-orthogonal tetrazole-PpIX click reaction, driving AuNP aggregation for deep-tissue PTT without the need of external light. EGCG-mediated mitochondrial targeting intensifies mitochondrial oxidative and thermal stress, further amplified by EQ-driven GSH depletion. This causes ATP depletion, HSP70 downregulation, ICD, and mtDNA release, which activates the cGAS-STING-PERK pathway, promotes ER stress and antitumor immunity, and inhibits lung metastasis. Collectively, this multimodal nanoplatform remodels TME into a hypoxia-alleviated, M1 macrophage-rich, and Treg-suppressed proinflammatory state, achieving efficacious eradication of tumor and inhibition of pulmonary metastasis in vivo.