Kidney-targeted drug delivery: from physiological mechanisms to precision therapeutics

Chronic kidney disease (CKD) and acute kidney injury (AKI) remain critical global health challenges, yet effective pharmacotherapies are severely limited by poor renal bioavailability and off-target systemic toxicity. Overcoming these obstacles requires a deep integration of renal physiopathology with advanced drug delivery engineering. This review provides a comprehensive analysis of the mechanisms governing kidney-targeted drug delivery. We first dissect the unique physiological barriers that dictate renal drug disposition, including the size- and charge-selective glomerular filtration barrier ("the sieve") and the high-capacity reabsorption machinery of the proximal tubule (e.g., megalin-mediated endocytosis). Subsequently, we elucidate the pathological alterations in the "fibrotic niche", highlighting emerging therapeutic targets such as the upregulated CD44 receptor and specific integrins on myofibroblasts. Based on this understanding, we systematically categorize current delivery strategies into two paradigms: (1) Passive Targeting, which exploits physicochemical properties (e.g., 75-100 nm size range for mesangial sequestration); and (2) Active Targeting, which utilizes ligand-receptor precision to direct carriers to the tubular epithelium (via megalin or transporters) or the fibrotic microenvironment (via hyaluronic acid or RGD [Arg-Gly-Asp]). Finally, we discuss the challenges of clinical translation, including interspecies differences and long-term nanotoxicology, and outline future directions in bio-inspired vectors and stimuli-responsive logic-gated systems. Ultimately, the seamless integration of these modular delivery platforms with patient-specific molecular signatures heralds a new era of precision nephrology, moving beyond systemic management toward site-specific interventions that may fundamentally reverse the progression of renal failure.