MiR-93-5p Loaded Lipid Nanoparticles Break the Dry Eye Vicious Cycle via Targeting MAP3K8

Dry eye disease (DED) is a prevalent ocular disorder characterized by tear film hyperosmolarity and sustained inflammation, which triggers a vicious cycle of corneal damage. Although mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown therapeutic potential, their efficacy as a standalone treatment remains limited, and the underlying mechanisms are still unclear, which hinders the development of targeted therapies. Here we demonstrate that limbal MSC-EVs (LMSC-EVs) mitigate hyperosmolar stress (HS)-induced damage in corneal epithelial cells (CECs). This effect was primarily mediated by the delivery of miR-93-5p, which targeted MAP3K8 and suppressed the pro-inflammatory pathway. Notably, superior therapeutic outcomes were achieved using synthetic mannosylerythritol lipid A (MEL-A)-based lipid nanoparticles (LNPs) loaded with miR-93-5p (miR93-LNPs), which significantly alleviated DED symptoms in a mouse model. Mechanistically, we delineated a coherent pathogenic pathway linking HS to CEC inflammation and apoptosis via the TRPV1/ROS/PI3K/Akt/HIF-1α/MAP3K8/p38/NF-κB signaling axis. Our findings provide insights into the molecular mechanisms of DED pathogenesis and highlight miR93-LNPs as a promising cell-free nanotherapeutic strategy for effective DED treatment by breaking its vicious cycle.