Orally delivered Perilla frutescens-derived nanovesicles regulate the gut-kidney biointerface to attenuate hyperuricemia-associated renal injury.

Hyperuricemia-associated renal injury involves coordinated disturbances in urate transport, tubular inflammation, and gut-kidney metabolic homeostasis. Here, we evaluated Perilla frutescens-derived exosome-like nanovesicles (PLENs) as an orally deliverable natural vesicle platform for this condition. PLENs showed stable nanoscale vesicular features and maintained structural compatibility under simulated gastrointestinal conditions. In potassium oxonate/hypoxanthine-induced hyperuricemic mice, oral PLENs reduced urate burden, preserved renal function, and alleviated tubular injury and early fibrotic remodeling. Mechanistically, PLENs improved renal urate transporter balance by restoring ABCG2 and suppressing URAT1/GLUT9, accompanied by reduced NLRP3-associated inflammatory stress. Fluorescence imaging supported a gastrointestinal-dominant exposure pattern, consistent with an intestine-facing mode of action. PLENs also strengthened colonic barrier integrity, remodeled intestinal urate transporter expression, reshaped cecal dysbiosis, restored major short-chain fatty acid outputs, and redirected intestinal metabolic pathways related to fermentation, redox regulation, amino acid metabolism, and ABC transport. These findings identify PLENs as oral natural nanovesicles that mitigate hyperuricemia-associated renal injury through integrated regulation of renal urate handling and the gut-kidney biointerface.