Chrysanthemum indicum L.-derived extracellular vesicles enhance the therapeutic efficacy of cyclosporine a against dry eye disease.

The pathological progression of dry eye disease (DED) involves a vicious cycle of oxidative stress and inflammation, posing a critical therapeutic challenge. Conventional therapies, such as cyclosporine A (CsA), are limited by poor corneal permeability and low ocular bioavailability. Here, we developed a novel, biocompatible nano-eye drop formulation using Chrysanthemum indicum L.-derived extracellular vesicles (CELNs) as a natural nanocarrier to engineer CsA-loaded CELNs (CsA@CELNs) for synergistic DED therapy. By combining CsA-mediated immunoregulation with enhanced corneal permeability and the intrinsic antioxidant and anti-inflammatory activities of CELN, the CsA@CELNs effectively disrupts the core pathogenic feedback loop of DED. In vitro and in vivo data demonstrated that a one-week, twice daily topical treatment with CsA@CELNs alleviated oxidative stress by scavenging reactive oxygen species (ROS) and activating the Nrf2/HO-1/NQO1 signaling pathway, while concurrently suppressing inflammation through inhibiting the NF-κB pathway and promoting macrophage repolarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. In a murine DED model, CsA@CELNs eye drop significantly restored tear secretion, promoted regeneration of corneal and conjunctival cells, and improved lacrimal gland histology. This multi-targeting CsA@CELNs system not only provides a safe and effective nanotherapeutic strategy for DED but also establishes plant-derived extracellular vesicles as a promising drug delivery platform for treating ocular surface and other inflammatory diseases.