Epigenetic Remodeling Hydrogel Patches for Multidrug‐Resistant Triple‐Negative Breast Cancer

Abstract The induced expansion of tumor‐initiating cells (T‐ICs) upon repeated exposure of tumors to chemotherapeutic drugs forms a major cause for chemoresistance and cancer metastasis. Here, a tumor‐microenvironment‐responsive hydrogel patch is designed to modulate the plasticity of T‐ICs in triple‐negative breast cancer (TNBC), which is insensitive to hormone‐ and HER2‐targeting. The on‐site formation of the hydrogel network patches tumors in a chemoresistant TNBC murine model and senses intratumoral reactive oxygen species for linker cleavage and payload release. Patch‐mediated inhibition of the histone demethylase lysine‐specific demethylase 1 (LSD1) epigenetically regulates the switch of T‐ICs from self‐renewal to differentiation, rehabilitating their chemosensitivity. Moreover, the hydrogel patch enhances tumor immunogenicity and increases T‐cell infiltration via epigenetic activation of innate immunity. A single‐dose of the hydrogel patch harboring LSD1 inhibitor and chemotherapy agent efficiently suppresses tumor growth, postsurgical relapse, and metastasis. The superior efficacy against multidrug resistance further reveals the broad applicability of epigenetic remodeling hydrogel patches.