Engineering a Multifunctional Nanozyme Platform for Synergistic Melanoma Therapy: Integrating Enzyme Activity, Immune Activation, and Low‐Temperature Photothermal Effects

Abstract Melanoma is characterized by rapid growth and high invasiveness, resulting in an exceptionally high malignancy and a significant propensity for metastasis. Current therapeutic modalities, such as chemotherapy and radiotherapy, exhibit limited efficacy due to severe side effects and immunosuppressive effects. Consequently, the development of precise and effective integrated therapeutic strategies is of paramount importance. Here, we report a multifunctional and multienzyme active nanosystem (FeCP@PDA‐GOx) that synergistically integrates starvation therapy, chemodynamic therapy, mild photothermal therapy (mPTT), and immunotherapy to achieve multidimensional therapeutic effects. This nanoplatform harnesses the enzymatic activities of glucose oxidase, peroxidase, oxidase, and catalase to enhance tumor microenvironment modulation and drug delivery efficiency, ultimately inducing ferroptosis in tumor cells. The system also establishes a positive feedback loop to further amplify its catalytic performance. Additionally, it effectively suppresses the expression of heat shock proteins in tumor cells, thereby augmenting the therapeutic efficacy of mPTT. Moreover, the system activates robust immune responses, suppressing lung metastasis and eliciting systemic antitumor effects to inhibit the growth of distal tumors. Experimental results demonstrate that this multifunctional nanoplatform exhibits exceptional therapeutic efficacy and safety in melanoma treatment, laying a solid foundation for the advancement of personalized medicine and intelligent therapeutic strategies.