Copper coordinated nanozyme-assisted photodynamic therapy for potentiating PD-1 blockade through amplifying oxidative stress

Induction of immunogenic tumor cell death (ICD) is a promising strategy to potentiate immune checkpoint blockade (ICB) efficacy. However, it is still a huge challenge to develop efficient ICD-inducing nanomedicine. Herein, a copper nanozyme-assisted photodynamic therapy (PDT) nanoplatform nHACI was developed to achieve efficient ICD induction and robust systemic antitumor immune response through amplifying intracellular oxidative stress. The nHACI was fabricated from hydrazided hyaluronan and Cu2+ through an innovative hydrazide-copper coordination and in situ mineralization process, followed by loading of photosensitizer indocyanine green (ICG) via ICG-copper coordination. The nHACI exhibited superior drug loading efficiency, tumor microenvironment-responsive degradation behavior, and Fenton-like, glutathione oxidase-like and catalase-like triple activities. Importantly, it could not only deplete glutathione and concurrently generate 1O2 and ·OH that amplified oxidative stress and induced ICD but also downregulate the proportion of M2 macrophages in tumors. The combination of nHACI-based PDT and PD-1 blockade could efficiently eradicate primary tumors, inhibit distant tumor growth and lung metastasis, and prevent tumor recurrence, demonstrating activation of robust systemic antitumor immune response. Collectively, this study presents a novel coordination assembly approach and nHACI holds great potential in eradicating primary tumors and potentiating ICB therapy via inducing ICD.