Kidney-targeted delivery of rapamycin via folic acid-Mn3O4 nanoparticles for acute kidney injury therapy.

Acute kidney injury (AKI) is a critical clinical syndrome characterized by an abrupt decline in renal function and is associated with substantial morbidity and mortality. Current therapeutic options remain predominantly supportive. Cisplatin-induced AKI, a clinically relevant subtype of AKI, is driven by oxidative stress, mitochondrial dysfunction, inflammatory activation, and tubular epithelial cell injury. Rapamycin, a potent mechanistic target of rapamycin (mTOR) inhibitor, has shown renoprotective potential in preclinical AKI models; however, its therapeutic application is limited by poor renal accumulation, low aqueous solubility, a narrow therapeutic window, and potential systemic toxicity. To address these limitations, a kidney-targeted nanotherapeutic was engineered by loading rapamycin onto ultrasmall manganese oxide (Mn3O4) nanoparticles surface-functionalized with folic acid (RAP@Mn3O4-FA). This nanoplatform integrates the intrinsic ROS-scavenging activity of Mn3O4 with folate receptor (FR)-mediated renal targeting, thereby enhancing intrarenal drug delivery while reducing off-target exposure. In a cisplatin-induced AKI mouse model, RAP@Mn3O4-FA improved renal function, attenuated histological injury, activated AMPK/mTOR-associated autophagy, and showed a favorable preliminary biosafety profile. These findings suggest that RAP@Mn3O4-FA is a promising kidney-targeted nanotherapeutic candidate for cisplatin-induced AKI treatment.