Multifunctional Biomaterial Strategies to Regulate Inflammation and Promote Kidney Repair.

Chronic kidney disease (CKD) involves inflammation, fibrosis, and impaired regeneration. We developed a biofunctional hybrid scaffold (PMEAR/MM/uEV) combining a porous poly(lactic-co-glycolic acid)-porcine extracellular matrix, ricinoleic acid-modified magnesium hydroxide, metanephric mesenchyme-like cells, and ureteric bud-derived extracellular vesicles, with resveratrol and adapalene to confer antioxidant and pro-regenerative properties. The scaffold exhibited uniform porosity, pH-buffering, and reactive oxygen species-scavenging activity. In vitro, it accelerated epithelial wound closure, reduced oxidative stress, and shifted cytokine profiles toward an anti-inflammatory state by increasing interleukin-4 while decreasing tumor necrosis factor-alpha, interleukin-6, and interleukin-8. In a 5/6 nephrectomy mouse model, PMEAR/MM/uEV reduced collagen deposition, improved blood urea nitrogen and creatinine, and up-regulated podocyte markers synaptopodin, nephrin, and podocin, as well as the renal developmental marker Pax2. mRNA sequencing revealed activation of angiogenesis, extracellular matrix remodeling, oxidative defense, and immune modulation, with Kyoto Encyclopedia of Genes and Genomes enrichment in tumor necrosis factor and interleukin-17 signaling and nuclear factor kappa B-associated pathways. These findings establish PMEAR/MM/uEV as an effective, multimodal platform for kidney regeneration.