Construction of multifunctional nanozymes with amplified immunogenic death effect as a long-term anti-tumor nanoplatform

Stimulating the immunogenic cell death (ICD) effect is a method of tumor treatment through activating immunity. While conventional approaches including chemotherapy, photothermal therapy (PTT), and chemodynamic therapy (CDT), demonstrate partial ICD induction capabilities, their efficacy in eliciting systemic immune responses remains constrained by the immunosuppressive tumor microenvironment. Herein, a trimetallic nanozyme (Mn/Fe-MIL-101/CuS/DOX@FA) was engineered through the integration of Mn-doped Fe-MOFs, CuS, doxorubicin (DOX, 35.08 mg/g), and folic acid (FA). The design leverages the synergistic effects of Mn(II), Fe(III), and Cu(II), combined with the photothermal performance of CuS, which collectively enhance glutathione peroxidase (GPx)-like and peroxidase (POD)-like activities. This catalytic cascade depletes glutathione and boosts hydroxyl radicals via Fenton-like reactions, thereby disrupting redox balance to amplify chemodynamic therapy. CuS-mediated photothermal effects coupled with pH/GSH-responsive DOX release further augment ICD, effectively reversing immunosuppression. In vivo evaluations demonstrated 57 % inhibition of the primary tumor and 66.7 % inhibition of the distant tumor, confirming its efficacy in tumor treatment and prevention of recurrence/metastasis. Besides, magnetic resonance imaging experiments showed the T₁/T₂ dual-mode imaging performance. Thereby, a long-term anti-tumor nanoplatform is constructed through dual-mode imaging-guided multimodal therapy, which integrates tumor diagnosis, treatment, and prevention of recurrence and metastasis.