Multiscale molecular modeling–directed ROS-responsive nanotherapy for dual-axis regulation of fibrotic and inflammatory signaling in alport nephropathy

BACKGROUND: In Alport nephropathy, tightly interconnected fibrotic, inflammatory, and oxidative cascades are activated, elevating reactive oxygen species (ROS) that intensify renal injury. The broad activation of stress-responsive and profibrotic pathways further induces disease progression and limits the efficacy of monotherapies. RESULTS: mice, PPCK + IG exhibited selective renal accumulation, oxidative activation, and robust suppression of fibrotic (α-SMA, fibronectin, and p-Smad2/3) and inflammatory markers (p-JNK, IL-6, and MCP-1), as well as downstream ERK attenuation, significantly improving renal function. CONCLUSIONS: The findings of our study demonstrate precision nanotherapy that exploits pathological oxidative stress for targeted delivery and the coordinated modulation of epigenetic and MAPK pathways, offering a promising strategy for Alport nephropathy and other chronic kidney diseases.