A high-entropy nanozyme-based photothermal-adjuvant in situ nanovaccine for potentiated tumor immunotherapy†

Nanozymes with peroxidase (POD)-like activity hold great promise for in situ nanovaccines to activate antitumor immunity through immunogenic cell death (ICD). However, their efficacy remains limited due to suboptimal reactive oxygen species (ROS) generation and the immunosuppressive tumor microenvironment (TME). To address this, we herein constructed a high-entropy nanozyme (HEzyme) using a Prussian blue analog (PBA) as the platform. The HE mixing state induced lattice distortion and d-orbital modulation, endowing the PBA-based HEzyme with an enhanced POD-like activity and an exceptional photothermal conversion efficiency of 82.96%. This dual functionality enabled photothermal-adjuvant ROS amplification for triggering robust ICD-driven anti-tumor immunity. Simultaneously, the HEzyme reprogrammed tumor-associated macrophages from immunosuppressive M2 to antitumor M1 phenotypes, reversing TME immunosuppression. In 4T1 tumor-bearing mouse models, the HEzyme-based in situ nanovaccine achieved dual suppression of primary and distal tumors. This work presents an innovative paradigm for engineering nanozyme-based in situ nanovaccines by introduction of HE into PBA, bridging photothermal intervention, ICD induction, and TME remodeling to potentiate tumor immunotherapy.