Celastrol-loaded micelles with dual-mucoadhesive strategy for efficient suppression of corneal neovascularization

Corneal neovascularization (CNV), a major cause of vision impairment, requires improved therapeutic strategies. While Celastrol (Cel), a natural product extracted from traditional Chinese herbs, demonstrates anti-angiogenic potential for CNV treatment, its clinical application can be hindered by poor aqueous solubility and ocular bioavailability. To address this, we developed mucoadhesive micelles using phenylboronic acid (PBA)- and stearic acid (SA)-modified chitosan oligosaccharides (COS) for encapsulation and enhanced ocular delivery of Cel. The Cel-loaded micelles (COSA-PBA@Cel) exhibited a positive Zeta potential of approximately +27 mV, facilitating electrostatic interaction with negatively charged ocular mucin. PBA integration further enabled dynamic covalent bonding with sialic acid residues, synergistically prolonging corneal retention. Therefore, COSA-PBA@Cel nanomicelles exhibited remarkably prolonged ocular surface retention time. In vitro experiments demonstrated that COSA-PBA@Cel micelles effectively inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs), showcasing potent anti-neovascular activity. In a mouse model of alkali burn-induced CNV, COSA-PBA@Cel micelles significantly suppressed pathological angiogenesis, primarily through enhanced Cel delivery that modulates the HIF-1α/VEGF signaling pathway. This nanoplatform overcomes key ocular drug delivery challenges while leveraging Cel's therapeutic potential, offering a promising topical solution for CNV management.