Engineered macrophage-targeted germacrone-bearing nanosheet achieves sequential treatment of acute kidney injury through macrophage polarization regulation and oxidative stress

Acute kidney injury (AKI) is a life-threatening clinical syndrome marked by a rapid decline in renal function, contributing to substantial morbidity and mortality. Emerging evidence suggests that modulating macrophage polarization represents a promising therapeutic strategy for AKI. However, achieving precise pharmacological regulation remains a challenge. To address this, we developed a novel macrophage-targeting nanoplatform (GMO@GO@PEG@MAN) by loading germacrone onto mannose-functionalized graphene oxide nanosheets. This engineered system enhances renal accumulation and enables macrophage-specific delivery in AKI models, while significantly suppressing pro-inflammatory M1 macrophage polarization. It provides multi-mechanistic renal protection by attenuating oxidative stress, promoting NRF2 nuclear translocation, inhibiting ferroptosis, and exerting potent broad-spectrum antimicrobial activity against both extracellular and intracellular pathogens. Our findings establish this nanoplatform as an effective multi-targeted therapy for AKI, demonstrating robust efficacy across both in vitro and in vivo models. This synergistic therapeutic strategy—combining macrophage reprogramming, oxidative stress mitigation, and antimicrobial activity—marks a significant advancement in AKI treatment paradigms.