Biodegradable ROS-Responsive TPCD Nanoparticles Mitigate Cisplatin-Induced Acute Kidney Injury via Synergistic Antioxidant and Immunomodulatory Actions

Abstract

Background Acute kidney injury (AKI) is a serious condition with high incidence and mortality rates, yet effective clinical treatment options remain limited. The therapeutic efficacy of small-molecule antioxidants such as N-acetylcysteine (NAC) is limited by their difficulty in targeting the kidneys and their rapid clearance. Nanomedicine platforms capable of simultaneously scavenging reactive oxygen species (ROS) and modulating inflammation offer new hope for the treatment of AKI. Methods We employed a previously reported TPCD conjugate (β-cyclodextrin co-functionalized with Tempol and phenylboronic acid pinacol ester), which self-assembles into nanoparticles (TPCD NPs). Its ROS-scavenging, anti-inflammatory, and cytoprotective activities were evaluated in vitro. In a cisplatin-induced AKI mouse model, TPCD NPs were administered intravenously, and their efficacy was compared with that of NAC. Renal function (serum creatinine, BUN), histopathology, tubular apoptosis, inflammatory cytokines (TNF-α, IL-6), and macrophage polarization were assessed. In vivo fluorescence imaging was used to monitor their biodistribution and assess short-term safety. Results TPCD NPs effectively scavenged ROS, reduced apoptosis, and suppressed inflammatory responses in vitro. In vivo, TPCD NPs significantly lowered serum creatinine and BUN levels, attenuated tubular injury and apoptosis, and decreased renal TNF-α and IL-6 levels compared with the model group and, in several endpoints, with NAC. The nanoparticles promoted macrophage polarization toward the reparative M2 phenotype. Fluorescence imaging revealed increased accumulation in injured kidneys, although renal retention was relatively short. Biocompatibility studies indicated acceptable short-term tolerability. Conclusion TPCD NPs demonstrate renoprotective effects in cisplatin-induced AKI, likely via combined antioxidant, anti-apoptotic, and immunomodulatory actions. However, the observed renal accumulation requires further quantitative pharmacokinetic validation, and long-term safety and efficacy in other AKI models remain to be established. This study suggests that TPCD NPs are a promising preclinical candidate for AKI, but clinical translation claims should be made with caution.