High Entropy 2D Layered Double Hydroxide Nanosheet Toward Cascaded Nanozyme-Initiated Chemodynamic and Immune Synergistic Therapy.

High-entropy nanomaterials (HEMs) are a hot topic in the fields of energy and catalysis. However, in terms of promising biomedical applications, potential therapeutic studies involving HEMs are unprecedented. Herein, we demonstrated high entropy two-dimensional layered double hydroxide () nanoplatforms with versatile physicochemical advantages that reprogram the tumor microenvironment (TME) and provide antitumor treatment via cascaded nanoenzyme-initiated chemodynamic and immune synergistic therapy. In response to the TME, the multifunctional sequentially release metal ions, such as Co, Fe, and Cu, exhibiting exquisite superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPX) activities. The multiple enzymatic activities convert specific tumor metabolites into a continuous supply of cytotoxic reactive oxygen species (ROS) to relieve hypoxia under a TME. Thus, facilitate robust nanozyme-initiated chemodynamic therapy (NCDT), achieving high therapeutic efficacy without obvious side effects. In addition, the release of Zn from the matrix triggers the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) signaling pathway, boosting the innate immunotherapeutic efficacy. The intratumoral applications of the nanocomposite in tumor-bearing mice models indicate that -mediated NCDT and immune synergistic therapy effectively upregulated the expression of relevant antitumor cytokines and induced cytotoxic T lymphocyte infiltration, showing superior efficacy in inhibiting tumor growth. Therefore, this work opens a new research direction toward synchronized NCDT and immunotherapy of tumors using HEMs for advanced healthcare.