E-Selectin-Targeted Nanomicelles via Sialic Acid Conjugation for Anti-Inflammatory Efficacy and Alleviating the Progression of Metabolic-Associated Steatotic Liver Disease

<b>Background:</b> Metabolic-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis (MASH), is a growing health concern characterized by liver inflammation, fibrosis, and endothelial dysfunction. Targeted therapies are essential to address these issues and improve treatment outcomes. <b>Methods:</b> A sialic acid (SA)-modified nanomicelle system (SA-PEG-ALA) was developed to target liver sinusoidal endothelial cells (LSECs) via the E-selectin (SELE). Molecular docking and surface plasmon resonance (SPR) were used to confirm the binding interaction between SA and SELE. In vitro assays using LSECs and steatotic hepatocytes were conducted to evaluate the cellular uptake and therapeutic efficacy of SA-PEG-ALA. In vivo studies using an HFHC-induced MASH mouse model were carried out to evaluate the distribution and therapeutic outcomes of SA-PEG-ALA. Additionally, RNA sequencing was performed to explore the molecular mechanisms underlying its effects. <b>Results:</b> Molecular docking and SPR analyses confirmed that SA effectively binds to SELE, facilitating the targeted delivery of ALA to LSECs. In vitro, SA-PEG-ALA showed substantially higher uptake in LSECs compared to other formulations. In vivo, SA-PEG-ALA demonstrated superior targeting of the liver and showed enhanced therapeutic effects compared to PEG-ALA, significantly alleviating steatosis, liver inflammation, and fibrosis in the MASH model. Mechanistically, SA-PEG-ALA interacted with HSP70, enhancing its stability and promoting the binding of HSP70 to IκBα, which contributed to inhibition of NF-κB signaling pathway. <b>Conclusion:</b> SA-PEG-ALA offers a promising targeted therapeutic strategy for MASLD, with improved liver targeting, anti-inflammatory, and antifibrotic effects, highlighting its potential for treating MASLD.