Nanomedicine-Driven Precision Therapy for Renal Fibrosis: From Mechanistic Insights to Kidney-Targeted Interventions.

Renal fibrosis acts as the convergent and irreversible pathological endpoint driving chronic kidney disease (CKD) to end-stage renal disease. Characterized by aberrant extracellular matrix (ECM) deposition and parenchymal architecture disintegration, this process is orchestrated by a dynamic multicellular network involving myofibroblast activation, metabolic reprogramming, and intricate crosstalk among signaling hubs like TGF-β/Smad and Wnt/β-catenin. While cornerstone therapies, such as renin-angiotensin system inhibitors (RASI) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, retard progression, they face significant bottlenecks, notably the inability to reverse established fibrosis and the risk of off-target systemic toxicity. Nanomedicine offers a precision-engineering approach to surmount these physiological barriers. By leveraging spatiotemporal control, intelligent nanocarriers facilitate kidney-targeted delivery and microenvironment-responsive release, while functional nanomaterials exert intrinsic antioxidative and anti-fibrotic bioactivity to reshape the fibrotic niche. This review systematically delineates the molecular landscape of renal fibrosis-with particular attention to emerging drivers such as epigenetic regulation and ferroptosis-and critically examines the translational hurdles of current strategies. Integrating molecular insights with nanotechnological innovation, we discuss how nanomedicine can potentiate therapeutic efficacy and enable phenotype-specific precision interventions. Finally, we provide a forward-looking perspective on overcoming clinical barriers and constructing integrated theranostic and regenerative platforms.