Nanoparticle-Mediated and Nanoengineered Drug Delivery for Glaucoma: Preclinical Evidence, Early Human Feasibility, and Translational Challenges

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Abstract
The management of glaucoma with drugs is mostly via the topical route, although these treatments have poor ocular bioavailability. Other problems limiting their therapeutic effect include pre-corneal clearance, corneal and ocular surface barriers, and the need for a long-term treatment regimen. Nanoparticle-mediated drug-delivery systems have shown the potential, particularly in preclinical studies, to improve ocular penetration and precorneal retention and to facilitate controlled drug release, with the aim of reducing dosing frequency. In this narrative review, the researchers focus on various nanoparticle-based approaches for sustained intraocular pressure control in glaucoma. The review encompasses carrier-based nanosystems, drug nanocrystals and nanosuspensions, nanoscale permeability or surface modifiers, multiscale nano-enabled formulations, and nanoparticle- or nanocarrier-integrated delivery devices. These approaches are designed to deliver conventional and innovative ocular hypotensive agents. Pharmacokinetics, corneal permeability, drug stability, tolerability, and duration of action of intraocular pressure-lowering drugs are critically reviewed across a predominantly preclinical evidence base; the two small human studies identified (n = 6 and n = 17) support clinical feasibility but do not establish durable clinical effectiveness, long-term safety, adherence benefit, or prevention of glaucoma progression. This review distinguishes improvements in ocular drug disposition from demonstrated IOP-lowering benefit and separates preclinical proof of concept from human evidence by applying an evidence-stratified formulation–performance framework rather than ranking nanocarriers by material class or isolated physicochemical properties. The available evidence is dominated by drugs that lower IOP, which in turn distinguishes prolonged control of IOP from any direct disease-modifying or neuroprotective action, for which glaucoma-specific evidence remains substantially more limited. The review further assesses the obstacles to clinical translation, including long-term safety, manufacturing reproducibility, sterilization, regulatory requirements, and patient and treatment burden. Generally, nanoengineered systems are promising platforms to address pharmacokinetic and treatment-delivery limitations of conventional glaucoma therapy, but comparative clinical effectiveness, long-term safety, adherence benefit, cost-effectiveness, and meaningful effects on glaucoma progression remain insufficiently demonstrated.

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