A mechanistic study on the SIRT3/RORγt/STAT3-regulated Th17-targeted bionic black phosphorus quantum dot cluster...

Sepsis-related acute kidney injury (SA-AKI) represents a severe complication associated with elevated mortality rates, primarily driven by imbalanced Th17 immune responses and mitochondrial dysfunction. Consequently, there is an urgent need for a versatile nanomaterial that can enhance mitochondrial performance while also exerting anti-inflammatory effects. A synthetically produced nanoenzyme has the potential to address this challenge. In this study, we created a biomimetic nanozyme (BPQDs@Raw264.7@Kim-1) by engineering clusters of black phosphorus quantum dots (BPQDs) that are coated with macrophage membranes and functionalized with kidney injury molecule-1 (Kim-1) for targeted delivery. This nanozyme improves its antioxidant and anti-inflammatory properties by clustering black phosphorus quantum dots, while the stability of the drug is maintained through encapsulation within Raw264.7 cell membranes. The system effectively achieves homologous targeting via external Kim-1 molecules. The objective of this nanozyme is to modulate the SIRT3/RORγt/STAT3 pathway to reduce Th17-driven inflammation and alleviate SA-AKI. In vitro experiments demonstrated that the nanozyme possesses excellent biocompatibility, efficient cellular uptake, and the ability to scavenge reactive oxygen species (ROS) in LPS-stimulated HK-2 cells. It mitigated mitochondrial injury, decreased apoptosis, and lowered the levels of pro-inflammatory cytokines. Mechanistically, the nanozyme's overexpression of SIRT3 inhibited RORγt/STAT3 signaling, resulting in reduced Th17 differentiation and inflammatory cytokine release. Importantly, silencing SIRT3 negated these therapeutic benefits, underscoring its critical role. This research introduces a targeted nanozyme approach that alleviates SA-AKI by simultaneously restoring the mitochondrial balance and suppressing Th17 inflammation through the SIRT3/RORγt/STAT3 pathway, presenting a promising therapeutic strategy for organ injury caused by sepsis.