Nanozyme-mediated biocatalysis as a mitochondrial oxidative stress amplifier for tumor nanocatalytic immunotherapy

Nanozyme-mediated tumor catalytic therapy has recently garnered attention as a means of destroying tumor cells and eliciting anti-tumor immune responses. Herein, a copper-doped mesoporous polydopamine (CP) nanozyme modified with triphenylphosphine (TPP) and hyaluronic acid (HA) was designed as a mitochondrial oxidative stress amplifier (CPTH) for inducing apoptosis and promoting immune responses with the assistance of mild photothermal therapy. The density functional theory (DFT) revealed the superoxide dismutase-like reaction mechanism of nanozymes, and combined with 3-amino-1,2,4-triazole (AT, catalase inhibitor) to achieve the goal of increasing the source and reducing the off-target consumption of intra-mitochondrial H2O2. Meanwhile, CPTH-AT nanozyme was found to amplify mitochondrial oxidative stress by inducing powerful oxidative OH through intra-mitochondrial GSH consumption and exerting peroxidase-like activity. The induction of mitochondrial oxidative damage serves as a trigger for the release of tumor-associated antigens. Thus, CPTH-AT nanozyme combined with mild photothermal therapy caused substantial exposure of damage-associated molecular patterns, maximizing the incidence of tumor immunogenic cell death. Moreover, nanozymes further promoted the dendritic cells maturation and recruitment, increased the infiltration of cytotoxic T lymphocytes and helper T cells, and decreased the proportion of regulatory T cells. In brief, the mitochondria-targeted nanozyme-based biocatalytic immunotherapy combined with mild photothermal therapy represents a promising cancer therapeutic strategy, establishing new paradigms for improving the bio-applications of nanozymes.