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

A folate-targeted Mn 3 O 4 nanoplatform was developed for cisplatin-induced AKI. • The platform combined ROS scavenging with localized rapamycin delivery. • FA modification enhanced tubular cell uptake via an FR-associated mechanism. • RAP@Mn 3 O 4 -FA promoted AMPK/mTOR-associated autophagic flux. • Treatment improved renal function and showed progressive clearance within 120 h. 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 (Mn 3 O 4 ) nanoparticles surface-functionalized with folic acid (RAP@Mn 3 O 4 -FA). This nanoplatform integrates the intrinsic ROS-scavenging activity of Mn 3 O 4 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@Mn 3 O 4 -FA improved renal function, attenuated histological injury, activated AMPK/mTOR-associated autophagy, and showed a favorable preliminary biosafety profile. These findings suggest that RAP@Mn 3 O 4 -FA is a promising kidney-targeted nanotherapeutic candidate for cisplatin-induced AKI treatment.