Dual‐Nanoparticle Engineered Hydrogel Reverses Bicellular Oxidative Stress to Accelerate Diabetic Fracture Healing

Abstract Impaired fracture healing in diabetic patients poses a persistent clinical challenge, with underlying mechanisms that remain to be fully elucidated. These findings reveal that high glucose microenvironments generate excessive reactive oxygen species in bone marrow mesenchymal stem cells (BMSCs) and bone marrow‐derived macrophages (BMDMs), leading to mitochondrial dysfunction and metabolic impairment. These pathophysiological disruptions suppress osteogenic differentiation in BMSCs while driving pro‐inflammatory polarization in BMDMs, processes closely tied to high‐glucose‐induced inhibition of Adenosine 5′‐monophosphate‐activated protein kinase (AMPK) phosphorylation. Restoration of AMPK phosphorylation emerges as a pivotal strategy to mitigate oxidative stress and restore cellular function. To address this, a dual‐targeted therapeutic system (DLNPs@HA hydrogel) is developed that combines anti‐CD105‐antibody‐modified nanoliposomes and phosphatidylserine‐modified nanoliposomes, both encapsulating the specific AMPK activator α‐lipoic acid. This hydrogel facilitates sustained nanoparticle release, enabling precise and effective delivery to BMSCs and BMDMs. In vitro, DLNPs@HA hydrogel successfully enhances osteogenic activity and suppresses inflammatory responses. In vivo, it accelerates fracture healing in diabetic mice. By precisely targeting BMSCs and BMDMs and reversing bicellular oxidative stress, this integrative medical‐engineering strategy provides a promising and translatable solution for diabetic fracture repair, seamlessly bridging mechanistic insights with therapeutic innovation.