Layer‐by‐Layer Assembly of Renal‐Targeted Polymeric Nanoparticles for Robust Arginase‐2 Knockdown and Contrast‐Induced Acute Kidney Injury Prevention

The mitochondrial enzyme arginase‐2 (Arg‐2) is implicated in the pathophysiology of contrast‐induced acute kidney injury (CI‐AKI). Therefore, Arg‐2 represents a candid target for CI‐AKI prevention. Here, layer‐by‐layer (LbL) assembled renal‐targeting polymeric nanoparticles are developed to efficiently deliver small interfering RNA (siRNA), knockdown Arg‐2 expression in renal tubules, and prevention of CI‐AKI is evaluated. First, near‐infrared dye‐loaded poly(lactic‐co‐glycolic acid) (PLGA) anionic cores are electrostatically coated with cationic chitosan (CS) to facilitate the adsorption and stabilization of Arg‐2 siRNA. Next, nanoparticles are coated with anionic hyaluronan (HA) to provide protection against siRNA leakage and shielding against early clearance. Sequential electrostatic layering of CS and HA improves loading capacity of Arg‐2 siRNA and yields LbL‐assembled nanoparticles. Renal targeting and accumulation is enhanced by modifying the outermost layer of HA with a kidney targeting peptide (HA‐KTP). The resultant kidney‐targeting and siRNA loaded nanoparticles (PLGA/CS/HA‐KTP siRNA) exhibit proprietary accumulation in kidneys and proximal tubular cells at 24 h post‐tail vein injection. In iohexol‐induced in vitro and in vivo CI‐AKI models, PLGA/CS/HA‐KTP siRNA delivery alleviates oxidative and nitrification stress, and rescues mitochondrial dysfunction while reducing apoptosis, thereby demonstrating a robust and satisfactory therapeutic effect. Thus, PLGA/CS/HA‐KTP siRNA nanoparticles offer a promising candidate therapy to protect against CI‐AKI. Utilizing electrostatic layer‐by‐layer adsorption between polymers and arginase‐2 (Arg‐2) small interfering RNA (siRNA), the delivery system of poly(lactic‐co‐glycolic acid)/chitosan/siRNA/hyaluronan and surface decoration with kidney targeting peptide (KTP) achieves high renal selectivity through KTP‐megalin and hyaluronan‐CD44 interactions. Specific silencing of renal tubule Arg‐2 mitigates oxidative/nitrifying stress and apoptosis, restores mitochondrial homeostasis, and achieves prevention of contrast‐induced acute kidney injury.