Spatiotemporally coordinated immunometabolic-hyperthermia therapy for diabetic bone defect regeneration

Diabetic bone defects (DBDs) are typified by persistent inflammation, oxidative stress, and microbial infection within the diabetic microenvironment, which collectively hinder osteogenesis and angiogenesis. Herein, we introduce an Immunometabolic-Hyperthermia Therapy (IMHT) strategy based on a dual-functional nanoplatform, namely a polydopamine/itaconate-incorporated agarose/gelatin (PIAG) hydrogel. This system is fabricated by incorporating itaconic acid (ITA) into polydopamine (PDA) nanoparticles through in situ polymerization, followed by encapsulation within a gelatin/agarose matrix. ITA primarily provides immunometabolic regulation, while PDA enables a tunable photothermal response. Upon localized photothermal heating (∼50 °C), the PIAG hydrogel effectively disrupts bacterial biofilms, with photothermal treatment providing the dominant antibacterial effect and ITA offering an additional supportive contribution. Upon mild photothermal activation (∼41 °C), IMHT mitigates excessive reactive oxygen species (ROS) generation, inhibits neutrophil extracellular trap (NET) formation, and reprograms macrophages toward an M2-like reparative phenotype through JAK1/STAT1 pathway inhibition. The resulting pro-regenerative immune milieu enhances fibroblast growth factor-2 (FGF-2) secretion, while heat-induced activation of HSP90 stabilizes FGF-2/FGFR1 signaling, further promoting osteogenic differentiation and endothelial migration. Overall, the spatiotemporally coordinated antibacterial, immunometabolic, and regenerative regulation realized by IMHT offers a comprehensive and effective strategy for the repair of diabetic bone defects.