Synergistic tumor microenvironment modulation enabled by a nanozyme-boosted biomimetic macrophage-derived nanovesicle for highly efficient antitumor therapy

Rationale: The tumor microenvironment (TME) plays a pivotal role in cancer progression, with tumor-associated macrophages (TAMs) serving as key contributors. Immunosuppressive M2-type TAMs are associated with poor prognosis and treatment resistance, highlighting the need for strategies to reprogram these cells into pro-inflammatory M1 phenotypes. To address this, we developed a TME-reshaping nanoplatform combining the tumor-targeting capability of M1 macrophage-derived nanovesicles (M1NVs) with the immunomodulatory and catalytic properties of hollow, virus-spiky hMnOx nanozymes. This approach aims to enhance chemotherapy delivery while simultaneously reversing immunosuppression and boosting antitumor immunity. Methods: We engineered a biomimetic nanoplatform by physically co-extruding M1NVs with hMnOx nanozymes. The platform was evaluated in a malignant melanoma model characterized by M2 TAM infiltration, using the first-line chemotherapeutic agent dacarbazine (DTIC) as a model drug. The system's tumor-targeting ability, cytotoxicity, and immunomodulatory effects were assessed. Additionally, the capacity of hMnOx nanozymes to induce immunogenic cell death (ICD) and promote antigen presentation was investigated. Results: The nanoplatform demonstrated precise tumor-targeted delivery of DTIC via M1NVs, effectively inducing tumor cell death. The combination of M1NVs and hMnOx nanozymes successfully repolarized M2 TAMs into pro-inflammatory M1 macrophages, alleviating immunosuppression and enhancing immunotherapy efficacy. Furthermore, hMnOx nanozymes triggered ICD and improved antigen presentation, amplifying antitumor immune responses. The fabrication process was simple and scalable, underscoring the platform's potential for clinical translation. Conclusion: This study presents a novel nanozyme-boosted biomimetic macrophage-derived nanovesicle system that integrates precise tumor targeting, chemotherapy delivery, and TME immunomodulation. By repolarizing TAMs and enhancing antitumor immunity, the platform offers a promising strategy to overcome treatment resistance in immunosuppressive tumors. Its scalable production and high clinical potential make it a viable candidate for future cancer therapy applications.