Fe-flavonoid nanozyme as dual modulator of oxidative stress and autophagy for acute kidney injury repair.

Background

Acute kidney injury (AKI), marked by a high mortality rate, remains a significant clinical challenge owing to limited therapeutic options. Oxidative stress is a key driver of AKI pathogenesis, underscoring the urgent need for innovative interventions. Recent advances demonstrate the potential of reshaping the oxidative stress microenvironment and activating intracellular autophagy to facilitate tissue repair. Nanotechnology-based antioxidants are emerging as promising approaches for AKI. Here, we present a novel nanoscale natural antioxidant platform for AKI treatment, incorporating reactive oxygen species (ROS) scavenging, oxidative stress modulation, anti-inflammatory properties and autophagy activation, which leverages these synergistic functions and lays the groundwork for clinical translation of next-generation nanotherapeutics in AKI.

Methods

We synthesized a Fe-flavonoid nanozyme (FD@BSA) composed of ferric chloride hexahydrate, dihydromyricetin (DMY), and bovine serum albumin (BSA). FD@BSA integrated DMY's antioxidant and autophagy-activating functions with iron-mediated catalytic activity. Its therapeutic efficacy was evaluated in two oxidative stress-driven renal injury models: H2O2-induced ROS overload in human renal proximal tubular epithelial (HK-2) cells and glycerol-mediated AKI mice. Mechanistic studies employed laser confocal microscopy to visualize intracellular ROS scavenging and autophagy activation, while Western blotting and immunohistochemistry assessed protein expression and tissue-level pathology.

Results

After intravenous administration, FD@BSA nanozyme selectively accumulated in the kidneys of water-restricted, glycerol-induced AKI mice. In vitro studies demonstrated that FD@BSA significantly decreased ROS accumulation in HK-2 cells, enhanced cell viability, attenuated inflammatory responses, and induced mitophagy, thereby preserving cellular homeostasis and alleviating injury. In vivo, FD@BSA treatment markedly ameliorated glycerol-induced AKI. Mechanistically, this protective effect was mediated by inhibition of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and upregulation of light chain 3 (LC3)-dependent autophagy, which together reduced ROS-driven cellular damage and mitigated renal injury, highlighting FD@BSA as a promising strategy for AKI.

Conclusion

This study establishes FD@BSA nanozyme as a versatile nanotherapeutic platform for AKI, which can effectively remodel the oxidative stress microenvironment by scavenging excessive ROS and activating intracellular autophagy. Such multifunctionality extends FD@BSA's applicability beyond AKI to other ROS-driven pathologies, positioning it as a next-generation, nanotechnology-based strategy for the treatment of oxidative stress-related diseases.