Natural <i>Spirulina Platensis</i> Dressing Promotes Diabetic Wound Repair via Mitigating Inflammation, Clearing Advanced Glycation End Products, and Stimulating Angiogenesis

Chronic nonhealing wounds pose a significant and growing global healthcare burden, particularly in the diabetic population, where impaired healing often leads to severe complications like ulceration and amputation. The pathophysiology is multifactorial, but two interconnected barriers, the accumulation of advanced glycation end products (AGEs) that hinder revascularization, and a persistent pro-inflammatory state driven by classically activated (M1) macrophages, are widely recognized as central to the impaired healing cascade. We therefore hypothesized that Spirulina platensis (SP), a natural microalga, could offer a multifaceted therapeutic strategy by concurrently targeting AGEs clearance and macrophage polarization to restore the healing microenvironment. This study aimed to validate SP's intrinsic bioactivities and engineer it into a functional hydrogel dressing for the management of diabetic wounds. We first characterized SP's effects in vitro through assays for AGEs depletion, fibroblast migration, endothelial tubulogenesis, and macrophage phenotype reprogramming. Subsequently, we incorporated SP into a three-dimensional (3D) hydrogel to create an SP-gel dressing and evaluated its efficacy in a high-fat-high-sugar and streptozotocin-induced diabetic rat wound model in vivo. Our results demonstrated that SP not only effectively cleared AGEs and enhanced cellular functions critical for repair but also skewed macrophages from an M1 to an alternatively activated (M2) phenotype, resolving inflammation. In vivo, the SP-gel dressing robustly accelerated wound closure by synergistically mitigating inflammation, reducing AGEs burden, stimulating angiogenesis, and promoting re-epithelialization. This work establishes the natural product SP as a potent, dual-targeting agent and its hydrogel formulation as a promising integrated therapy, highlighting a translatable and holistic approach for diabetic wound healing with potential applications in broader regenerative medicine contexts.