A living therapeutic material to coordinate metabolic oxygenation and regenerative signaling in diabetic wounds.

Abstract

Diabetic chronic wounds remain difficult to treat because hypoxia and insufficient regenerative signaling persist. Although live biotherapeutics offer a promising route to local oxygenation therapy, current methods largely support a single microbial function rather than coordinate microbial oxygenation with regenerative cues. Here, we report a hydrogel living therapeutic material in which a crosslinked hyaluronic acid matrix coordinates a living metabolic module of Synechococcus elongatus with a regenerative module of platelet-rich plasma (PRP). The matrix enables injectability and rapid gelation while supporting microbial metabolic activity and modulating the local retention and release of PRP-derived growth factors. The resulting material sustains oxygen generation and preserves the viability of the living module. Particularly, it reduces intracellular ROS accumulation, promotes fibroblast migration, and enhances endothelial tube formation in vitro. In diabetic wounds, it accelerates wound closure and improves re-epithelialization, collagen remodeling, and angiogenesis. Transcriptomic analysis further reveals coordinated regulation of stimulus-response, immune-related, and cytokine- and chemokine-associated pathways. This work establishes a living therapeutic material framework for integrating microbial oxygenation with regenerative signaling for pathological wound microenvironment remodeling. STATEMENT OF SIGNIFICANCE: Diabetic wounds are difficult to heal because damaged tissues often lack both oxygen and regenerative signals. Current living wound therapies mainly focus on microbial oxygen production, but they rarely coordinate oxygen supply with growth-factor-mediated tissue repair. This study develops an injectable living hydrogel that combines photosynthetic Synechococcus elongatus with platelet-rich plasma in a hyaluronic acid matrix. The material continuously generates oxygen, retains and releases regenerative factors, reduces oxidative stress, and promotes cell migration, angiogenesis, collagen remodeling, and wound closure. By integrating metabolic oxygenation with regenerative signaling, this work provides a strategy for remodeling pathological wound microenvironments and designing living therapeutic materials for chronic tissue repair.