Potent Polydopamine-Based Cascade Nanozyme as ROS Amplifier for Triple Photothermal-Catalytic- Chemotherapy

Nanozyme-based catalytic therapy has emerged as a promising cancer treatment strategy by converting endogenous substrates into tumor-damaging reactive oxygen species (ROS). However, the efficacy of nanozymes is significantly hindered by the scarcity of hydrogen peroxide (H₂O₂) within the tumor microenvironment (TME). In this study, we developed multifunctional nanozyme nanoparticles (FeDD) with photothermally enhanced multienzyme cascade catalysis, which could synergistically trigger tumor cell apoptosis through photothermal therapy (PTT), catalytic therapy, and chemotherapy. The FeDD were self-assembled from iron-coordinated polydopamine (PDA) and doxorubicin (DOX), exhibiting superoxide dismutase (SOD)-, peroxidase (POD)-, and glutathione peroxidase (GPx)-like activities. We reported the novel finding that PDA possessed intrinsic SOD-mimetic activity, which catalyzed the superoxide anions (•O₂^-) into H₂O₂ and O₂, thereby self-supplying the H₂O₂ for subsequent reactions while alleviating tumor hypoxia. Concurrently, the iron coordination sites exhibited POD-like activity, enabling them to efficiently catalyze the conversion of in situ-generated H₂O₂ into highly cytotoxic hydroxyl radicals (•OH). The GPx-like activity further depleted intracellular glutathione (GSH), amplifying oxidative stress and minimizing ROS scavenging. Beyond its chemotherapeutic effect, the encapsulated DOX enhanced NADPH oxidase (NOx) activity, promoting NADPH oxidation and generating additional •O₂^- to sustain the catalytic cascade. Moreover, the photothermal effect mediated by polydopamine (PDA) under near-infrared (NIR) synergistically enhanced the overall therapeutic efficacy. In vitro and in vivo antitumor efficacy studies have revealed that FeDD nanozyme could effectively inhibit the development of tumors while maintaining a high level of biocompatibility. Upon NIR irradiation, FeDD achieved a killing rate against 4T1 cells in vitro while enabling complete tumor eradication in vivo. Collectively, FeDD emerges as a promising nanoplatform for PTT-enhanced cascade catalytic tumor therapy, offering a novel approach to enhancing treatment efficacy.