Targeted Sirtuin 3 Activation by Biomimetic Black Phosphorus Nanosheets Mitigates Sepsis-Induced Acute Kidney Injury through Yeast Mitochondrial Escape 1-Like 1 Deacetylation.

Abstract

Sepsis-induced acute kidney injury (AKI) is characterized by mitochondrial dysfunction and dysregulated inflammation, with a lack of effective therapies. Studies have found that down-regulation of Sirtuin 3 (Sirt3) expression in renal tubular epithelial cells is associated with mitochondrial imbalance, suggesting its potential as a therapeutic target. Based on this, the research team developed a targeted nanodelivery system: black phosphorus nanosheets loaded with a cortistatin agonist were encapsulated with macrophage membranes modified with (KKEEE)₃K peptides to specifically deliver Sirt3-activating components to the kidneys. This nanosystem demonstrated favorable stability and biocompatibility. Ex vivo experiments confirmed its ability to alleviate lipopolysaccharide-induced oxidative stress, apoptosis, and inflammation in HK-2 cells, while restoring mitochondrial function. Mechanistically, the nanomaterial regulates mitochondrial homeostasis by activating the Sirt3-YME1L1 deacetylation axis. This study provides a novel nano-therapeutic strategy for sepsis-induced AKI, combining targeting capability with metabolism regulation, and holds broad implications for the treatment of inflammatory organ damage.