A renal-targeted gene delivery system derived from spermidine for arginase-2 silencing and synergistic attenuation of drug-induced acute kidney injury

Drug-induced acute kidney injury (DI-AKI) presents a substantial clinical challenge with limited therapeutic options. This study investigate the potential of arginase-2 (Arg-2) as a therapeutic target for DI-AKI, and developed a multifunctional gene delivery system with renal targetability for Arg-2 silencing. Clinical data from DI-AKI patients and bioinformatics data from mice confirmed the upregulation of Arg-2 in DI-AKI, highlighting its potential as a therapeutic target. To downregulate Arg-2 expression, a siRNA-based approach utilizing a cationic polymer carrier, PSPD, was developed. PSPD, synthesized using spermidine (SPD) as a monomer, demonstrated efficient siRNA condensation, high loading capacity, protection against degradation, and pH-responsive release. Furthermore, PSPD exhibited intrinsic multifunctionalities derived from SPD, synergizing with siRNA to enhance DI-AKI alleviation through mechanisms such as promoting mitochondrial autophagy, mitigating oxidative stress, and inhibiting apoptosis. To enhance renal targeting, a kidney targeting peptide-modified hyaluronic acid (HA-KTP) shell layer was then coated on the PSPD/siRNA complex, and the resulting HA-KTP/PSPD/siRNA showed a slight size increase with a marked change in surface charge from positive to neutral. KTP modification improved the recognition of nanoparticles by renal tubular epithelial cells, thereby enhancing targetability. The constructed delivery system demonstrated potent therapeutic efficacy in a DI-AKI animal model. This work highlights the potential of Arg-2 inhibition as a promising strategy for DI-AKI therapy, and demonstrates the efficacy of the HA-KTP/PSPD/siRNA delivery system for targeted renal treatment.