Kidney-Targeted Cilastatin Nanoparticles Inhibit DPEP1-Mediated Ferroptosis for Acute Kidney Injury Therapy.

Cisplatin-induced acute kidney injury (CI-AKI) is a frequent, dose-dependent complication in patients receiving cisplatin chemotherapy, and effective targeted treatments remain unavailable. The development of targeted therapies for CI-AKI may improve the efficacy of chemotherapy while mitigating renal toxicity. Given that ferroptosis is a key pathological mechanism in CI-AKI, targeted drug delivery systems against this process represent a promising therapeutic strategy. Dipeptidase 1 (DPEP1) is highly expressed in renal proximal tubular brush borders and has been associated with ferroptosis regulation and tubular injury. In this study, mesoporous polydopamine nanoparticles (MPDA NPs) were engineered for renal-targeted delivery of cilastatin sodium (CTT), a specific DPEP1 inhibitor, through L-serine (L-Ser) surface modification (CTT/MPDA@L-Ser NPs). In vitro experiments demonstrated that CTT/MPDA@L-Ser NPs inhibited the expression of DPEP1 to upregulate the expression of the ferroptosis-suppressing protein glutathione peroxidase 4 (GPX4), thereby suppressing ferroptosis pathways. In AKI mice, CTT/MPDA@L-Ser NPs exhibited selective renal accumulation, significantly ameliorating serum creatinine and blood urea nitrogen levels. Collectively, CTT/MPDA@L-Ser NPs exhibited potent therapeutic efficacy against AKI, presenting a promising strategy for targeted AKI management.