Melanin-Deferoxamine Nanoparticles Targeting Ferroptosis Mitigate Acute Kidney Injury via RONS Scavenging and Iron Ion Chelation.

Rhabdomyolysis (RM)-induced acute kidney injury (AKI) involves the release of large amounts of iron ions from excess myoglobin in the kidneys, which mediates the overproduction of reactive species with the onset of iron overload via the Fenton reaction, thus inducing ferroptosis and leading to renal dysfunction. Unfortunately, there are no effective treatments for AKI other than supportive care. Herein, we developed a multifunctional nanoplatform (MPD) by covalently bonding melanin nanoparticles (MP NPs) to deferoxamine. The nanoplatform has good dispersion and physiological stability, excellent chelating performance to iron ions, and broad-spectrum reactive species scavenging activity. Furthermore, cellular experiments showed that the NPs possessed high biocompatibility, antiapoptotic activity, antioxidant properties, and strong scavenging capacity of Fe to mitigate iron overload, protecting the intracellular mitochondria from oxidative stress. Meanwhile, the intrinsic photoacoustic imaging capability of melanin allows the real-time monitoring of MPD NPs' target uptake and metabolic behavior in healthy and AKI mice. Most importantly, MPD NPs led to downregulation of the antioxidant pathway by targeting ferroptosis, thus effectively rescuing renal function in vivo, mitigating oxidative stress and inflammatory responses, and inhibiting renal tubular cell apoptosis. The nanoplatform offers a novel therapeutic strategy for RM-induced AKI.