Dual-targeting nanozyme combined with aPD-L1-based immunotherapy for combating cancer recurrence and metastasis

The heterogeneity of tumor microenvironment (TME) and existence of cancer stem cells (CSCs) severely impede the therapeutic efficacy of current anti-tumor treatments, which is regarded as the culprit of tumor recurrence and metastasis. Herein, a TME-responsive nanoplatform based on manganese dioxide (MnO2) nanozyme was proposed for synergistic anti-tumor therapy. Dihydroartemisinin (DHA), an effective ferroptosis-inducer that possesses good reactive oxygen species-producing ability and immunological cell death-triggering property, was loaded in hollow MnO2 nanoparticles, which was further coated with polymetformin/hyaluronic acid (HA) to obtain MDPH nanozyme. Due to the catalase-like features of MnO2 nanozyme, more oxygen was produced while more glutathione was consumed in TME, facilitating DHA-mediated chemodynamic therapy (CDT). Meanwhile, MDPH nanozyme specifically targeted both tumor cells and CSCs owing to the active targetability of HA towards CD44 receptor. The ferroptosis induced by MDPH nanozyme efficaciously inhibited CSCs that are more sensitive to ferroptotic therapy but often resistant to conventional treatment regimens. By combining with aPD-L1-based immunotherapy, MDPH nanozyme efficiently suppressed 4 T1 breast tumor growth, decreased tumor stemness and reshaped immunosuppressive TME, remarkably preventing tumor relapse and metastasis. Therefore, this strategy provides a perspective and feasible approach for precise anti-tumor therapy through focusing on CSCs elimination and combined CDT/immunotherapy.