Tumor microenvironment-responsive cascaded nanozyme-based composite hydrogel for multi-modility synergistic therapies in cancer treatment

• An injectable nanocomposite hydrogel was constructed using AuPt NPs and 8arm-PEG-thiol, loaded with OXA. • Robust immobilization of AuPt NPs was achieved through the covalent crosslinking with 8arm-PEG-thiol. • The nanocomposite hydrogel exhibited excellent photothermal effect, cascade nanozyme activities, and OXA-induced ICD for TME remodeling. • Synergistic therapeutic effects of chemo-photothermal therapy, chemodynamic therapy, and immunotherapy were successfully achieved in 4 T1 tumor-bearing mice models. Multifunctional nanomedicine offers a promising approach for anticancer therapy but systemic delivery faces challenges due to biological barriers. To overcome this, we developed a tumor microenvironment (TME)-responsive injectable nanocomposite hydrogel (AuPt NPs@OXA gel) for synergistic cancer therapy. The hydrogel was synthesized via metal-sulfur bonding between AuPt nanoparticles and 8arm-PEG-thiol, with oxaliplatin (OXA) encapsulated. Under near-infrared irradiation, AuPt NPs exhibited a robust photothermal effect, facilitating on-demand OXA release. The released OXA direct cytotoxic effects on tumor cells and triggered immunogenic cell death (ICD) in 4 T1 cells. Additionally, the glucose oxidase-like activity of AuPt NPs@OXA gel disrupted glucose metabolism, depleting glucose to produce gluconic acid and H 2 O 2 . Meanwhile, catalase-like and peroxidase-like activities catalyzed hydrogen peroxide to produce O 2 and reactive oxygen species (ROS), relieving tumor hypoxia and amplifying oxidative stress for enhancing chemodynamic therapy. In sum, the combined effects of chemotherapy, photothermal effect (PTT), chemodynamic therapy (CDT), and OXA-meidated immunotherapy exhibited significant tumor growth inhibition in vitro and in vivo. Thus, this study introduced a novel strategy for TME remodeling and localized synergistic cancer therapy, providing a pathway for improving anticancer outcomes.