Phenylboronate hydrogel for administration route tailored dual-drug delivery to anterior and posterior ocular segments.

Frequent multidrug eyedrop instillation for ocular perioperative prophylaxis (e.g., cataract surgery) suffers from rapid nasolacrimal clearance, limited corneal penetration, and poor access to the posterior segment. To address these limitations, we engineered an interface-adaptive phenylboronate ester hydrogel for rapid in situ gelation and the co-entrapment of two frequently instilled drugs (moxifloxacin and dexamethasone) in their free or liposomal forms at physiological pH. This platform utilizes chemical crosslinking between hyaluronic acid-conjugated 2-aminophenylboronic acid and the diols of polyvinyl alcohol (HA-2APBA@PVA), forming a dynamic hydrogel network via phenylboronate ester bonds with a thermodynamically favorable formation energy (ΔG = -10.64 kcal/mol). This unique chemistry imparts shear-thinning injectability through fine ophthalmic needles, ensures mechanical stability against blink-induced shearing, and drives robust mucoadhesion with tear film mucins such as MUC5AC for prolonged ocular retention at the injection site. Architecturally, a "liposome-in-gel" system establishes hierarchical diffusion steps that suppress the initial burst effect and extend drug release duration by >2-fold compared to the free-drug solution control. The hydrogel demonstrates excellent ophthalmic compatibility, exhibiting physiological osmolality, >80% optical transmittance, and near 100% viability in human corneal and retinal pigment epithelial cells. Safety was further validated via Draize irritation testing and preserved ocular histology across topical and periocular administration routes. Unlike the rapid washout of standard eyedrops, this hydrogel depot ensures prolonged ocular surface retention. Pharmacokinetic analysis revealed route-dependent versatility: compared to standard eyedrops, subconjunctival administration enhanced anterior segment exposure of moxifloxacin and dexamethasone by 14.9- and 8.6-fold, respectively, while sub-Tenon dosing facilitated targeted delivery to the posterior segment. This single, dynamic covalent chemistry provides a scalable, clinically compatible alternative strategy to eyedrops and advances multidrug therapies across both ocular segments.