© 2022 Elsevier B.V.Cisplatin is a potent and widely used chemotherapy agent, however, nephrotoxicity limits its use. Many patients need to pause or withdraw from chemotherapy to prevent acute kidney injury. To prevent cisplatin damage, we designed chitosan/siRNA nanoparticleswhich are nontoxic and are readily taken up by HEK293 cells. The nanoparticles contained siRNA against cationic membrane transport (OCT1&2) and apoptosis related proteins (p53, PKCδ, and γGT). In mice treated with cisplatin, serum creatinine levels increased from 15 to 88 mg/dL and blood urea nitrogen levels increased from 0.25 to 1.7 mg/dL, however, siRNA nanoparticles significantly limited these levels to 30 mg/dL and 0.55 mg/dL, respectively. Western and IHC analyses showed lower p53, PKCδ, and γGT expressions in siRNA treated mice. Histomorphological evaluation revealed high-level protection of kidney proximal tubules from cisplatin damage. Protein expressions and extent of kidney protection were directly correlated with number of siRNA applications. Our results suggest that this novel approach for kidney-targeted delivery of select siRNAs may represent a promising therapy for preventing cisplatin-induced nephrotoxicity. Furthermore, this or other similarly sized nanocarriers could potentially be utilized to passively target kidneys for diagnostic, protective, or treatment purposes.