Shaogang Wang, Na Zeng, Yuhan Wang, Yuanyuan Yang
Kidney-targeted drug delivery is pivotal for treating renal diseases while minimizing systemic toxicity. To navigate the organ's complex physiological barriers, advanced nanomedicines employ integrated strategies. Our comprehensive narrative review provides a structured analysis of these strategies through a dual lens: first, by examining the fundamental mechanisms of renal targeting-including passive filtration, active receptor-mediated uptake, and their synergistic combination; and second, by deconstructing delivery systems into several fundamental pillars, the carrier platforms, the functional moieties that confer targeting, responsiveness and special properties along with therapeutic cargo. We evaluate how polymeric nanoparticles, liposomes, and exosomes, when functionalized with peptides, antibodies, or biomimetic coatings, can achieve enhanced renal specificity. Furthermore, we discuss how microenvironmental triggers such as pH, reactive oxygen species, and enzymes enable precise spatiotemporal drug release at pathological sites. Despite significant progress, critical translational challenges remain, including overcoming hepatic sequestration, ensuring long-term biocompatibility, and addressing patient heterogeneity. Future advances will depend on combining multimodal targeting, real-time feedback, and scalable manufacturing processes. This review synthesizes current knowledge to offer a rational design framework for the next generation of intelligent kidney-targeted therapeutics.