A silk fibroin-based stimuli-responsive hydrogel enhances diabetic foot ulcer healing via the controlled release of Piezo1 agonists Yoda1

Diabetic foot ulcer (DFU) is highly prevalent and remains a major clinical challenge. It is characterized by impaired microvasculature, persistent oxidative stress, chronic infection, and immune dysregulation, which collectively lead to chronic non-healing wounds. The tibial cortex transverse transport (TTT) technique has been shown to enhance DFU healing by restoring distal limb perfusion, with Piezo1 likely acting as a key mediator in this signal transduction process. Inspired by this mechanism, we used the Piezo1 agonist Yoda1 to pharmacologically replicate the effects of TTT and investigate its therapeutic potential in enhancing diabetic wound repair. To address the poor water solubility and narrow therapeutic window of Yoda1, we encapsulated it in ROS-responsive micelles and further incorporated them into a stimuli-responsive hydrogel composed of silk fibroin (SF) and hyaluronic acid. The hydrogel was crosslinked via dynamic boronate ester bonds, conferring responsiveness to pH, ROS, and glucose, thereby enabling controlled, sustained drug release. In addition, short cationic antimicrobial peptides (AMPs) were modified with a C14 fatty acid chain to form self-assembling structures with enhanced stability and antimicrobial potency, which were then incorporated into the hydrogel. Within the pathological DFU microenvironment, the SF-based hydrogel gradually degraded, releasing AMPs and Yoda1 to exert synergistic therapeutic effects, including potent antimicrobial activity, attenuation of oxidative stress, promotion of M2 macrophage polarization, and enhanced angiogenesis. Comprehensive in vitro cellular assays and in vivo evaluations in a rat DFU model demonstrated significant therapeutic efficacy. Overall, these findings suggest that this multifunctional, stimuli-responsive, dual-nanoparticle delivery hydrogel represents a potential strategy for DFU treatment.