Nanotechnology-based ocular drug delivery systems: recent advances and future prospects

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TL;DR

This review summarizes recent advances in nanotechnology-based ocular drug delivery systems (ODDS), including nanomicelles, nanoparticles, nanoemulsions, liposomes, dendrimers, and microneedles, which can overcome ocular barriers and improve drug bioavailability. Traditional eye drops have less than 5% bioavailability due to tear turnover and corneal barriers, but nanocarriers can prolong drug retention, enhance permeability, and enable sustained release. The clinical significance lies in the potential of these systems to improve treatment for glaucoma, age-related macular degeneration, diabetic retinopathy, and dry eye disease, with several products already FDA-approved and many in clinical trials.

Full summary

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**Background:** The eye is a complex organ with static and dynamic barriers (e.g., tear film, cornea, blood-aqueous barrier, blood-retinal barrier) that limit drug delivery. Traditional topical eye drops have bioavailability typically less than 5%. Ocular diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and dry eye disease (DED) affect millions globally, with an estimated 2.2 billion people having visual impairment worldwide and an annual economic burden of $139 billion in the US. Nanotechnology offers new strategies to overcome these barriers and improve therapeutic outcomes.

**Methods:** This is a narrative review of novel ODDS reported in the past five years. The authors describe ocular anatomy and barriers, summarize traditional routes of administration (topical, subconjunctival, intracameral, intravitreal, retrobulbar, systemic), and discuss recent advances in nanocarriers including nanomicelles, nanoparticles (NPs), nanosuspensions, nanoemulsions (NEs), microemulsions, nanofibers, dendrimers, liposomes, niosomes, nanowafers, contact lenses, hydrogels, and microneedles (MNs). They also cover gene therapy (viral and non-viral vectors, antisense oligonucleotides, RNAi, CRISPR-Cas9), exosomes, and self-nano emulsifying drug delivery systems (SNEDDS). Physicochemical characterization parameters (particle size, zeta potential, pH, viscosity, osmolality, drug loading/release, biocompatibility) are discussed. The review includes tables of FDA-approved nanocarriers and clinical trials.

**Key Results:** The review highlights numerous preclinical and clinical examples. For instance, TPGS nanomicelles (approximately 13 nm) loaded with 5 mg/mL cyclosporine facilitated drug retention in cornea and sclera. Chitosan-coated PLGA NPs delivered bevacizumab with concentrations above 22 ng/mL for 6 weeks in posterior ocular tissues, and subconjunctival injection significantly reduced VEGF in retina for 12 weeks. Hollow PLA NPs with medium-thickness shell (~40 nm) sustained pilocarpine release and IOP reduction for more than 56 days in rabbit glaucoma model. A hybrid nanosuspension and dissolving MN system achieved transscleral deposition of triamcinolone acetonide of 56.46 ± 7.76 μg/mm², 4.5-fold higher than common drug-loaded MN. A nano-micelle system (nEPCs) delivered aflibercept to retina in laser-induced CNV mouse model. Dendrimer gel particles (nDHP, ~200 nm) increased corneal permeability by 17-fold and reduced IOP by 4.5 mmHg in 4 h, 2.6 times more effective than BT/PBS eye drops. In a rat corneal alkali burn model, a PUTK/RH patch reduced mean fluorescence intensity to 39.0 ± 6.7 AU vs. 53.4 ± 10.5 AU in alkaline burn group on day 3. A liposomal tacrolimus (FK506) eye drop with ~300 nm diameter and +30 mV surface charge reduced ROS and DED-related inflammatory factors. Exosomes from regulatory Treg cells conjugated with anti-VEGF antibodies showed 5-fold longer intraocular retention and 3.5-fold increased accumulation in CNV lesions. FDA-approved products include Visudyne® (liposomal verteporfin, 2000), Restasis® (nanoemulsion cyclosporine A, 2002), Cequa® (nanomicellar cyclosporine A, 2018), and Eysuvis® (nanosuspension loteprednol etabonate, 2020). Clinical trials include cyclosporine OTX-101 (Phase III), dexamethasone OCS-01 (Phase II), and liposomal latanoprost (Phase I/II).

**Clinical Implications:** Nanotechnology-based ODDS can significantly improve ocular drug bioavailability, prolong drug retention, reduce dosing frequency, and enhance patient compliance. These systems offer potential for treating both anterior segment diseases (e.g., DED, glaucoma, keratitis) and posterior segment diseases (e.g., AMD, DR, uveitis). Gene therapy and exosome-based approaches represent emerging frontiers. However, challenges remain including production complexity, stability, safety, targeting efficiency, and high manufacturing costs. Most research is still preclinical, and more in vivo studies in human-like models are needed. Despite these hurdles, the review concludes that nanocarriers are expected to become the main means of ocular drug therapy in the future.