Phototheranostic offers a regional-focused tumor treatment upon photoirradiation. However, it is difficult to completely eradicate solid tumors using a conventional phototheranostic owing to the residual tumor cells outside the laser irradiation range. Herein, we fabricated a metallopolysaccharide-based smart nanotheranostic (Fe– d HA) via a nanoassembly-driven method, in which Fe3+ ions were coordinated to dopamine-modified biopolysaccharide hyaluronic acid ( d HA). Taking advantage of the structural backbone and intrinsic dual-information-related functions of HA as well as the bi-functional Fe­(III)-coordination centers, Fe– d HA can efficiently target tumor cells for phototheranostic. Additionally, it can be activated by endogenous overexpressed hyaluronidase to achieve sequential ferroptosis in tumor cells. The precise imaging and effective tumor inhibition using this metallopolysaccharide-based nanotheranostic were significantly demonstrated in vivo and in vitro. Thus, this rationally designed Fe– d HA provided a simple metallopolysaccharide strategy to develop an “all-in-one” smart nanotheranostic to synergize different therapeutic modalities for improving cancer therapy.

Chemodynamic immunotherapy that utilizes catalysts to produce reactive oxygen species (ROS) for killing tumor cells and arousing antitumor immunity has received considerable attention. However, it is still restricted by low ROS production efficiency and insufficient immune activation, due to intricate redox homeostasis in the tumor microenvironment (TME). Herein, a metalloprotein‐like hybrid nanozyme (FeS@GOx) is designed by in situ growth of nanozyme (ferrous sulfide, FeS) in a natural enzyme (glucose oxidase, GOx) to amplify ROS cascade for boosting chemodynamic immunotherapy. In FeS@GOx, GOx allows the conversion of endogenous glucose to gluconic acid and hydrogen peroxide, which provides favorable increasing hydrogen peroxide for subsequent Fenton reaction of FeS nanozymes, thus reinforcing ROS production. Notably, hydrogen sulfide (H2S) release is activated by the gluconic acid generation‐related pH decrease, which can suppress the activity of endogenous thioredoxin reductase and catalase to further inhibit ROS elimination. Thus, FeS@GOx can sustainably amplify ROS accumulation and perturb intracellular redox homeostasis to improve chemodynamic therapy and trigger robust immunogenic cell death for effective immunotherapy combined with immune checkpoint blockade. This work proposes a feasible H2S amplified ROS cascade strategy employing a bioinspired hybrid nanozyme, providing a novel pathway to multi‐enzyme‐mediated TME modulation for precise and efficient chemodynamic immunotherapy.

Tumor imaging and photoimmunotherapy holds great promise for precise and efficient tumor treatment. However, tumor microenvironment (TME) with high redox level inhibits reactive oxygen species mediated-treatment and immune response. The...