Tumor Microenvironment‐Activated Fe3+‐Doped Dendritic Mesoporous Organosilica Nanocomposites as Ferroptosis Inducers for Enhanced Immunotherapy

Abstract Dendritic mesoporous organosilica (DMOS) nanoparticles are widely used to transport therapeutic agents to cancer sites and rapidly release them owing to their rapid biodegradability in the tumor microenvironment (TME). However, the role of these DMOS nanoparticles as nanocarriers is limited, and their applications remain relatively simple. In this study, Fe 3+ ‐doped dendritic mesoporous organosilica (Fe‐DMOS) nanoparticles are designed as a new type of ferroptosis inducer and are combined with sodium hyaluronate‐modified calcium peroxide to form TME‐responsive nanocomposites. The nanocomposites can effectively generate a large number of hydroxyl radicals through the Fenton reaction between the released Fe 3+ and self‐compensated hydrogen peroxide, and mitochondrial injury caused by Ca 2+ overload further promotes this process. Both Fe 3+ and disulfide bonds can induce glutathione depletion, thus downregulating the expression of glutathione peroxidase 4 and triggering lethal levels of lipid peroxidation products, further facilitating ferroptosis in tumor cells. Additionally, the ferroptosis‐mediated process of immunogenic cell death promotes a long‐term antitumor immune response to prevent metastasis of tumor cells with the assistance of an immune checkpoint inhibitor (anti‐PD‐1). Fe‐DMOS nanoparticles are synthesized with ferroptosis‐inducing capabilities and established TME‐responsive nanocomposites combined with an immune checkpoint inhibitor to effectively improve tumor immunotherapy.