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

Area of Science:

• Nephrology
• Nanomedicine
• Chemotherapy-induced Toxicity

Background:

• Cisplatin chemotherapy frequently causes acute kidney injury (AKI), a serious complication lacking targeted treatments.
• Ferroptosis, a form of regulated cell death, is a key mechanism driving CI-AKI.
• Dipeptidase 1 (DPEP1) is implicated in ferroptosis and renal tubular injury.

Purpose of the Study:

• To develop a targeted drug delivery system for CI-AKI management.
• To investigate the therapeutic potential of inhibiting DPEP1-mediated ferroptosis in CI-AKI.
• To evaluate the efficacy of novel mesoporous polydopamine nanoparticles loaded with cilastatin sodium.

Main Methods:

• Engineered mesoporous polydopamine nanoparticles (MPDA NPs) for renal targeting.
• Surface modification with L-serine (L-Ser) for targeted delivery of cilastatin sodium (CTT).
• In vitro studies on DPEP1 inhibition and ferroptosis pathway modulation (GPX4 expression).
• In vivo assessment in AKI mouse models to evaluate renal function and nanoparticle accumulation.

Main Results:

• CTT/MPDA@L-Ser NPs successfully inhibited DPEP1 expression in vitro.
• The nanoparticles upregulated glutathione peroxidase 4 (GPX4), suppressing ferroptosis.
• In AKI mice, CTT/MPDA@L-Ser NPs showed selective renal accumulation.
• Significant improvements in serum creatinine and blood urea nitrogen levels were observed in treated mice.

Conclusions:

• CTT/MPDA@L-Ser NPs demonstrate potent therapeutic efficacy against cisplatin-induced acute kidney injury.
• Targeted inhibition of ferroptosis via DPEP1 offers a promising strategy for CI-AKI management.
• This nanoparticle-based approach represents a potential advancement in mitigating chemotherapy-related nephrotoxicity.