Hyperuricemia-related diabetic wounds are notoriously difficult to treat due to elevated uric acid (UA) levels, excessive reactive oxygen species (ROS), and chronic inflammation. Current therapies often fail to address these underlying causes, underscoring the need for innovative approaches that not only clear UA but also mitigate inflammation and promote tissue regeneration. In this study, we developed a polyrotaxane-based microsphere (HPR MS) system conjugated with 4,5-diamino-2-thiouracil (DT) to achieve high-affinity UA clearance without increasing cytotoxicity. By leveraging the molecular motility of the polyrotaxane structure, featuring β-cyclodextrin (β-CD) shuttles along the F-127 axis, we significantly improved the molecular recognition between DT and UA for enhanced UA absorption efficiency. In vitro experiments confirmed that HPR/DT MS rapidly reduced UA levels compared to control groups. Using a type 2 diabetic wound model, HPR/DT MS treatment effectively reduced UA levels, suppressed COX-2 expression, and transformed the immune microenvironment from a pro-inflammatory to a regenerative state in vivo. This was accompanied by enhanced M2 macrophage polarization, angiogenesis, and improved blood perfusion, resulting in accelerated wound healing. Overall, these findings highlight HPR/DT MS as a promising therapeutic strategy for hyperuricemia-related diabetic wounds, targeting the core pathological factors to improve wound repair.
Keywords: 4,5-diamino-2-thiouracil; Diabetic wound healing; Polyrotaxane; Uric acid.
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