A Dual‐Bioresponsive and Programmable Microneedle Matrix as a Bioinspired Coupler for Orchestrating Diabetic Bone Regeneration

ABSTRACT Diabetic bone repair is impaired by a microenvironment characterized by heightened susceptibility to infection and persistent inflammation. This study presents a dissolvable, dual‐responsive (to glutathione and gelatinase) microneedle patch (CGF/PP@MN) for spatiotemporally controlled therapy. The system features a GelMA hydrogel matrix encapsulating Concentrated Growth Factors (CGF) within its core, while its surface is functionalized with a glutathione‐reactive anti‐inflammatory peptide (pro‐AIP) and a gelatinase‐cleavable antimicrobial peptide (pro‐AMP). This spatial design enables a sequential, pathology‐triggered release cascade: upon insertion, pro‐AMPs are first cleaved in the presence of bacterial gelatinase to eradicate biofilms; subsequently, the elevated glutathione concentration activates pro‐AIPs to mitigate inflammation and promote M2 macrophage polarization, thereby remodeling the hostile immune niche. Finally, the sustained release of CGF from the hydrogel core drives vascularization and osteogenesis. This platform demonstrates precise temporal alignment with endogenous healing, excellent biocompatibility, and robust bioactivity in vitro. In a diabetic bone defect model, it significantly enhanced wound healing, attenuated inflammation, promoted robust bone regeneration, and improved overall repair outcomes. This work provides a novel combinatorial strategy for immunomodulation and regenerative repair of diabetic bone defects.