Trace element-dictated exosome modules and self-adaptive dual-network hydrogel orchestrate diabetic foot regeneration through complement-mitochondria-autophagy circuitry

Abstract Background Diabetic foot ulcers (DFU), perpetually trapped in a vicious cycle of inflammation and ischemia, remain a significant clinical challenge. Exosomes (Exo) therapy holds promise for tissue repair, yet its functional potency and delivery efficiency are often limited. Methods We proposed an integrated strategy combining trace elements (TE) programming, Exo engineering, and intelligent delivery to overcome both functional and delivery constraints. Multiple TE (Fe, Mg, Zn, Mn, and Se) were incorporated into a three-dimensional (3D) dynamic culture system to construct high-activity engineered Exo (3D-TE-Exo). The biological mechanisms were explored via transcriptomics, mitochondrial function assays, and oxidative stress analyses. A dual-network hydrogel, incorporating dynamic Schiff base bonds and ultraviolet (UV)-triggered disulfide bond reorganization, was developed for precise and sustained Exo release in vivo. Results 3D-TE-Exo achieved a yield of 1.9 × 10 12 particles/ml, representing a 29-fold increase over conventional culture (6.5 × 10 10 particles/ml). These Exo modulated the complement pathway, restored mitochondrial membrane potential, enhanced adenosine triphosphate (ATP) production, and activated autophagy, thereby alleviating oxidative stress, with complement 1q binding protein (C1QBP) identified as a key mediator. The hydrogel enabled prolonged Exo retention and controlled release at the wound site. In DFU rat models, this system achieved 89.71% wound closure by day 14, significantly higher than the 50.64% observed in controls. Conclusions This study presents a synergistic approach integrating engineered Exo and smart biomaterials to accelerate DFU healing. The platform offers a multi-target intervention strategy with strong translational potential for the clinical management of chronic wounds.