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

Abstract

Abstract 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.