Biomimetic reactive oxygen/nitrogen nanoscavengers inhibit "ferroptosis storm" and modulate immune targeting for acute kidney injury.

Abstract

Cisplatin (Cis), a potent chemotherapeutic agent, often causes acute kidney injury (AKI), limiting its clinical efficacy. RONS flares at the AKI site are a key factor in its progression. In this study, leveraging the advantages of cell membrane-coated biomimetic nanocarriers, we developed a multifunctional biomimetic nanodelivery system nano-RONS-sacrificial agent for AKI treatment. Ferrostatin-1 (Fer-1) was conjugated with curcumin (Cur) via 4-carboxyphenylboronic acid (4-PBA) and fucoidan (Fuc) to construct a ROS-responsive nanodelivery system (FPPF@Cur), which was further coated with M2 macrophage membranes (M2M) to form the multifunctional biomimetic nano-RONS-sacrificial agent (M2FPPF@Cur) designed for targeted delivery of Cur to injured kidneys. M2FPPF@Cur demonstrated rapid accumulation in the injured kidneys with selective uptake and prolonged retention in injured kidneys, the ROS-responsive mechanism facilitated controlled drug release at the AKI site, reducing off-target effects and enhancing therapeutic efficacy, effectively scavenging RONS, reducing lipid peroxidation, and targeting GPX4 protein to inhibit "ferroptosis storm". It suppressed the expression of inflammation-related NF-κB/NLRP3 signaling pathway proteins and regulated the repolarization of macrophages from M1 to M2 phenotype to regulate inflammation. The results showed that injected M2FPPF@Cur specifically accumulated in the injured kidney and exerted good renoprotective effects ultimately preventing the progression of AKI.