Mitigation of Cisplatin-Induced\nNephrotoxicity and\nAugmentation of Anticancer Potency via Tea Polyphenol Nanoparticles’\nCodelivery of siRNA from CRISPR/Cas9 Screened Targets

Cisplatin, a frontline chemotherapeutic agent against\ncancer, faces\nchallenges in clinical application due to significant toxicities and\nsuboptimal efficacy. Renal toxicity, a dose-limiting factor of cisplatin,\nresults from multifactorial processes including cisplatin-induced\ncellular pyroptosis, oxidative damage, and inflammatory responses.\nOur findings reveal that Tea Polyphenols Nanoparticles (TPNs) derived\nfrom Epigallocatechin gallate (EGCG) effectively could address these\ndiverse mechanisms, comprehensively alleviating cisplatin-induced\nnephrotoxicity. Leveraging TPNs as carriers, chemical conjugation\nenables the encapsulation of tetravalent cisplatin prodrug, extending\nits systemic half-life, enhancing tumor tissue accumulation, while\nsimultaneously mitigating renal toxicity. Concurrently, employing\na CRISPR/Cas9 kinase library, we identified CSNK2A1 as a target sensitizing\ntumor cells to cisplatin, enabling specific siRNA sequences to augment\ncisplatin susceptibility, thereby minimizing the dosage requirement.\nBenefiting from the versatile carrier properties of TPNs to codeliver\ncisplatin prodrug and anti-CSNK2A1 siRNA, we developed a codelivery\nsystem, Pt-TPNs/siRNA. Pt-TPNs/siRNA not only enhances the anticancer\neffects but also mitigates cisplatin-induced renal toxicity, achieving\nefficacy while reducing toxicity. Mechanistic and safety assessments\nof these nanoparticles were conducted at both cellular and animal\nlevels, opening new avenues for improved clinical utilization of cisplatin.