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, we developed layer-by-layer (LbL) assembled renal-targeting polymeric nanoparticles to efficiently deliver small interfering RNA (siRNA), knockdown Arg-2 expression in renal tubules, and evaluated prevention of CI-AKI. Firstly, near-infrared dye-loaded poly(lactic-co-glycolic acid) (PLGA) anionic cores were electrostatically-coated with cationic chitosan (CS) to facilitate the adsorption and stabilization of Arg-2 siRNA. Next, nanoparticles were coated with anionic hyaluronan (HA) to provide protection against siRNA leakage and shielding against early clearance. Sequential layering of electrostatically adsorbed CS and HA improved loading capacity of Arg-2 siRNA and yielded LbL-assembled nanoparticles. Renal targeting and accumulation was enhanced by modifying the outermost layer of HA with a kidney targeting peptide (HA-KTP). The resultant PLGA/CS/HA-KTP siRNA nanoparticles exhibited proprietary accumulation in kidneys and proximal tubular cells at 24 hours post-tail vein injection. In iohexol-induced in vitro and in vivo CI-AKI models, PLGA/CS/HA-KTP siRNA nanoparticles alleviated oxidative and nitrification stress, and rescued 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. This article is protected by copyright. All rights reserved.