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. In this study, MPDA NPs were engineered to encapsulate CTT. To further increase renal accumulation of CTT, L‐serine was conjugated to the surface of the MPDA nanoparticles (CTT/MPDA@L‐Ser NPs). CTT/MPDA@L‐Ser NPs inhibit DPEP1 activity, thereby restoring ferroptosis defense mechanisms through upregulation of GPX4 and SLC7A11 expression, ultimately mitigating cisplatin‐induced AKI pathology.