High Entropy 2D Layered\nDouble Hydroxide Nanosheet\nToward Cascaded Nanozyme-Initiated Chemodynamic and Immune\nSynergistic Therapy

High-entropy nanomaterials (HEMs) are a hot topic in\nthe fields\nof energy and catalysis. However, in terms of promising biomedical\napplications, potential therapeutic studies involving HEMs are unprecedented.\nHerein, we demonstrated high entropy two-dimensional layered double\nhydroxide (<b>HE-LDH</b>) nanoplatforms with versatile physicochemical\nadvantages that reprogram the tumor microenvironment (TME) and provide\nantitumor treatment via cascaded nanoenzyme-initiated chemodynamic\nand immune synergistic therapy. In response to the TME, the multifunctional <b>HE-LDHs</b> sequentially release metal ions, such as Co<sup>2+</sup>, Fe<sup>3+</sup>, and Cu<sup>2+</sup>, exhibiting exquisite superoxide\ndismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPX)\nactivities. The multiple enzymatic activities convert specific tumor\nmetabolites into a continuous supply of cytotoxic reactive oxygen\nspecies (ROS) to relieve hypoxia under a TME. Thus, <b>HE-LDHs</b> facilitate robust nanozyme-initiated chemodynamic therapy (NCDT),\nachieving high therapeutic efficacy without obvious side effects.\nIn addition, the release of Zn<sup>2+</sup> from the <b>HE-LDH</b> matrix triggers the cyclic GMP-AMP synthase/stimulator of interferon\ngene (cGAS/STING) signaling pathway, boosting the innate immunotherapeutic\nefficacy. The intratumoral applications of the nanocomposite in tumor-bearing\nmice models indicate that <b>HE-LDH</b>-mediated NCDT and immune\nsynergistic therapy effectively upregulated the expression of relevant\nantitumor cytokines and induced cytotoxic T lymphocyte infiltration,\nshowing superior efficacy in inhibiting tumor growth. Therefore, this\nwork opens a new research direction toward synchronized NCDT and immunotherapy\nof tumors using HEMs for advanced healthcare.