Engineered Exosome‐Mediated FIH‐1 Delivery for Targeted Therapy of Hyperuricemic Nephropathy by Inhibiting NF‐κB/NLRP3 Inflammasome Signaling and Restoring Autophagic Homeostasis

ABSTRACT

Renal tubular epithelial fibrosis is a key pathological process in the progression of hyperuricemia (HUA), and hyperuricemic nephropathy (HN). Targeted inhibition of renal tubular epithelial cell (RTEC) fibrosis represents a promising therapeutic strategy for HN. Extracellular vesicles derived from induced pluripotent stem cell‐derived mesenchymal stem cells (iPSC‐MSCs) were engineered as nanostructured delivery vehicles incorporating two functional modules: a kidney‐targeting module and a functional protein module. The targeting module was constructed by anchoring cholesterol‐modified RTEC‐specific peptides onto the extracellular vesicle membrane to enhance selective accumulation in RTECs. The functional protein module consisted of extracellular vesicles enriched with factor inhibiting hypoxia‐inducible factor 1 (FIH‐1). Functional analyses demonstrated that FIH‐1 delivery effectively suppressed uric acid (UA)‐induced fibrotic responses by inhibiting activation of the NF‐κB/NLRP3 inflammasome signaling pathway and restoring dysregulated autophagy. These coordinated regulatory effects resulted in significant downregulation of renal tubular epithelial injury. The targeting capability and therapeutic efficacy of the engineered extracellular vesicle system were further validated in both in vitro and in vivo models of HUA‐associated renal injury. Collectively, these findings establish a targeted exosome‐based nanotherapeutic strategy for the precision treatment of HN and provide a conceptual framework for the development of next‐generation engineered extracellular vesicle platforms in regenerative medicine.