Biomimetic Black Phosphorus Nanosheets Mitigate Sepsis-Induced AKI via Sirtuin 3 Activation and YME1L1 Deacetylation

Sepsis-induced acute kidney injury (AKI) is a severe condition marked by mitochondrial dysfunction and dysregulated inflammation, lacking effective treatments. Current therapies often fail to address the underlying cellular damage. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, is downregulated in renal tubular epithelial cells during AKI, leading to mitochondrial imbalance. Activating Sirt3 presents a promising therapeutic strategy to restore mitochondrial health and combat inflammation in the kidneys. This study explores a targeted nanodelivery approach to address this critical gap.

The research team developed biomimetic black phosphorus nanosheets (BPNS) loaded with a cortistatin agonist. These were encapsulated with macrophage membranes modified with (KKEEE)₃K peptides for kidney-specific targeting. Ex vivo experiments used HK-2 cells (human kidney-2 tubular epithelial cells) to assess the nanosystem's ability to alleviate lipopolysaccharide (LPS)-induced oxidative stress, apoptosis, and inflammation. Mitochondrial function restoration was also evaluated as a key endpoint. The study confirmed favorable stability and biocompatibility of the nanosystem.

The targeted nanosystem demonstrated favorable stability and biocompatibility. Ex vivo, the nanosheets effectively alleviated LPS-induced oxidative stress, apoptosis, and inflammation in HK-2 cells. Crucially, they restored mitochondrial function, which is often severely compromised in AKI. This restoration suggests a reversal of the cellular damage characteristic of sepsis-induced AKI. The study confirmed the nanosystem's ability to mitigate multiple facets of cellular injury. The protective effects were attributed to a specific molecular mechanism.

Mechanistically, the nanomaterial regulated mitochondrial homeostasis by activating the Sirt3-YME1L1 deacetylation axis, indicating a direct molecular pathway for its therapeutic effects. This activation of Sirt3 led to the deacetylation of YME1L1 (Yeast Mitochondrial Escape 1-Like 1), a key protein involved in mitochondrial inner membrane proteolysis and quality control.