Microenvironment Responsive Self‐Powered Hydrogel for Electro‐Inspired Regeneration of Infectious Diabetic Bone Defects

ABSTRACT Hyperglycemia, excessive reactive oxygen species (ROS), and bacterial infection considerably hinder the regeneration of infected diabetic bone defects. Conventional tissue‐engineering strategies often lack spatiotemporal responsiveness to the pathological microenvironment or require external power sources for electrical stimulation. Inspired by enzymatic biofuel cell technology, this study introduces a microenvironment‐responsive self‐powered MXene‐based electroactive hydrogel (sp‐MEH) that uniquely integrates cascade catalysis with endogenous current generation under diabetic conditions. Unlike previously reported conductive hydrogels or piezoelectric materials, sp‐MEH autonomously consumes excess glucose and ROS while simultaneously producing sustained electrical signals without external energy input. This dual functionality enables three synergistic therapeutic actions: remodeling of the pathological chemical microenvironment to promote anti‐inflammatory macrophage polarization, activation of voltage‐gated Ca 2+ channels and downstream CaMKII/PKC pathways to enhance osteogenic differentiation, and interference with bacterial energy metabolism to achieve potent antibacterial effects. sp‐MEH significantly outperforms its non‐electroactive or randomly mixed counterparts in promoting the regeneration of infected diabetic bones, as validated in vitro and in vivo. This study establishes a paradigm for self‐powered, microenvironment‐adaptive biomaterials that convert pathological cues into therapeutic signals. Thus, it presents a transformative strategy for complex bone defect repair.