A pH-responsive ultrasmall Fe–kaempferol nanoplatform ameliorates acute kidney injury by enhancing efferocytosis and metabolic reprogramming

BACKGROUND: Acute kidney injury (AKI) remains a major clinical challenge and is largely driven by excessive oxidative stress, inflammatory responses, and tubular cell apoptosis. However, effective therapeutic strategies that simultaneously target these pathological processes are still lacking. RESULTS: We developed a pH-responsive ultrasmall Fe-kaempferol (Fe-Kae) nanoplatform with coordinated antioxidant and anti-inflammatory activities for AKI treatment. Owing to their ultrasmall size and pH-responsive properties, Fe-Kae nanoparticles preferentially accumulated in injured renal tissues and exhibited robust renoprotective effects in multiple murine AKI models, including ischemia-reperfusion injury, cisplatin-induced nephrotoxicity, and calcium oxalate-induced kidney injury. Integrated transcriptomic and metabolomic analyses of ischemia-reperfusion-injured kidneys revealed that Fe-Kae treatment markedly enhanced efferocytosis-associated pathways and induced coordinated metabolic reprogramming, characterized by optimized tricarboxylic acid cycle activity and enhanced glutathione metabolism. CONCLUSIONS: This study establishes a nanomedicine-based therapeutic strategy that couples efferocytosis enhancement with metabolic reprogramming to achieve effective renoprotection. Our findings highlight pH-responsive ultrasmall metal-polyphenol nanoplatforms as a promising paradigm for the treatment of AKI.