Navigating the Renal Bio–Nano Interface: Physicochemical Rules for Crossing Barriers and Cellular Transport

Abstract As a highly perfused and selective filtration organ, the kidney features complex, highly differentiated bio–nano interfaces. Conventional research focusing on organ homing largely prioritizes total renal drug exposure, yet therapeutic efficacy depends on crossing specific interfaces to meet pathological demands─aspects that remain poorly delineated. This review deconstructs the kidney into five serial bio–nano interfaces and defines the rules that govern nanoparticle fate at each of them. We then show how a kidney disease microenvironment rewrites these transport rules via interface reprogramming. Based on this, it outlines the corresponding delivery strategies tailored to three primary pathological modules. In glomerular diseases, spatial redistribution caused by barrier disruption is exploited for targeted entrapment. In tubular injury, the uptake decline from receptor downregulation is bypassed via basolateral pathways or uptake-independent extracellular interventions. In interstitial–vascular diseases, the transport barrier characterized by enhanced extravasation but restricted deep diffusion, resulting from microvascular leakage and fibrotic resistance, is overcome by leveraging microenvironmental features to build local drug reservoirs. Finally, considering translational hurdles and long-term retention risks, future material design must advance toward dynamic interface responsiveness, precise subcellular compartmentalization, and safe clearance. This framework aims to provide a physicochemical rationale for targeting distinct renal subregions and designing nanomedicines tailored to specific disease stages.