Zn2+-assisted dual functional flavonoid in ameliorating sepsis-associated acute kidney injury by regulating macrophage ferroptosis.

BACKGROUND

Sepsis-associated acute kidney injury (SA-AKI) is a common and severe complication of sepsis. Quercetin (Qu), a naturally occurring flavonoid with robust antioxidant and anti-inflammatory activities, mitigates AKI in pre-clinical models, yet its clinical utility is constrained by poor bioavailability and non-specific tissue distribution.

PURPOSE: To overcome the aforementioned limitations and precisely interrupt macrophage-driven SA-AKI pathogenesis, we developed macrophage membrane-encapsulated ZIF-8 quantum dots loaded with Qu (M-M@ZIF-8@QuQQD) that delivers Qu specifically to renal macrophages, and investigated its therapeutic mechanism.

STUDY

DESIGN

In vivo murine SA-AKI models and in vitro macrophage models, comparative efficacy and biodistribution were assessed between M-M@ZIF-8@QuQQD and free Qu. And the underlying protective mechanism of M-M@ZIF-8@QuQQD in SA-AKI was delineated.

METHODS

M-M@ZIF-8@QuQQD was synthesized and injected into SA-AKI mice; renal accumulation, macrophage targeting, kidney function, histological damage, oxidative stress, and inflammatory cytokines etc. were assessed. Following RNA sequencing, the underlying mechanism of M-M@ZIF-8@QuQQD in ameliorating SA-AKI was investigated in both in vitro and in vivo models.

RESULTS

Our findings demonstrated that M-M@ZIF-8@QuQQD exhibited strong renal accumulation and macrophage-specific targeting, resulting in enhanced renal protection. Transcriptomic analysis further revealed that the renal protective effects of M-M@ZIF-8@QuQQD were mediated through the inhibition of SLC7A11-regulated ferroptosis pathways.

CONCLUSION

By enabling macrophage-specific delivery of Qu and inhibiting ferroptosis, M-M@ZIF-8@QuQQD offer a mechanistically informed and clinically promising targeted strategy for the treatment of SA-AKI.