Mucoadhesive Cationic Liposome Nanoparticles Coated with Methacrylated Hyaluronic Acid for Ocular Drug Delivery

Drug delivery to the ocular surface remains challenging due to rapid tear turnover, limited corneal permeability, and the short residence time of conventional carriers. To address these limitations, nanoscale cationic liposomes were synthesized using microfluidic techniques and subsequently functionalized with methacrylated hyaluronic acid (HAMA) to improve mucoadhesion and ocular retention. HAMA, capable of forming both electrostatic and covalent interactions with mucins, markedly enhanced the adhesive performance of the liposomes. Optimization via a Taguchi orthogonal array produced uncoated liposomes with a mean diameter of 170 nm (PDI = 0.22, ζ = +51 mV), which increased to 285 nm (ζ = +24 mV) following HAMA coating, confirming successful nanoscale modification. In vitro mucin interaction studies revealed particle enlargement (∼498 nm) and charge reversal (ζ = −38 mV), consistent with strong mucoadhesive binding. Ex vivo retention on bovine conjunctival tissue demonstrated significantly greater adhesion for HAMA-coated liposomes compared with uncoated and HA-coated controls. Bevacizumab (BEV) release followed a diffusion-controlled profile over 48 h, fitting both Higuchi and Korsmeyer–Peppas models. Cytocompatibility in HCE-T cells indicated >75% viability across all formulations. Furthermore, CD44-mediated uptake assays confirmed enhanced internalization of HA- and HAMA-functionalized liposomes. Collectively, these findings establish HAMA-coated nanoliposomes as a promising, noninvasive platform for prolonged and targeted ocular delivery of biopharmaceuticals.