Organic Nanozyme‐Embedded Biotherapeutic Thermosensitive Hydrogel for Extracellular GSH Depletion and Postoperative Tumor Suppression

Postoperative tumor recurrence remains a major challenge in solid tumor treatment, largely attributed to an immunosuppressive tumor microenvironment and the enrichment of extracellular glutathione (GSH) in the tumor bed, which supports tumor cell survival and proliferation. To address these issues, we designed a multifunctional hydrogel (named SEH) loaded with a novel cyanine nanozyme and Escherichia coli (E. coli). The cyanine nanozyme integrates efficient photothermal therapy (PTT), photodynamic therapy (PDT), and peroxidase-like enzyme activity. SEH is a temperature-sensitive agarose hydrogel. Upon light irradiation, PTT and PDT are simultaneously triggered, inducing hydrogel degradation to release the encapsulated nanozymes and E. coli. PTT and PDT jointly kill residual tumor cells and E. coli, and the death of the latter leads to the release of pathogen-associated molecular patterns (PAMPs). The nanozymes combined with PDT cyclically produce more reactive oxygen species to deplete extracellular GSH, which disrupts the redox balance of residual tumor cells. Furthermore, released PAMPs recruit immune cells to the tumor site, thereby activating anti-tumor immune responses and establishing long-term immune protection. This study provides a novel and effective strategy for postoperative tumor therapy and recurrence inhibition.