Nanotechnological Advances in Ocular Therapeutics: A Narrative Review of Drug Delivery Platforms, Clinical Applications, and Translational Challenges

Abstract

Purpose

Nanotechnology-based ocular drug delivery systems offer a promising approach to overcoming the anatomical and physiological barriers that limit the efficacy of conventional ophthalmic formulations, where topical bioavailability typically remains below 5% owing to rapid nasolacrimal drainage, precorneal tear turnover, and corneal impermeability. This narrative review synthesises current evidence on nanocarrier design, delivery pathways, and disease-specific therapeutic applications, incorporating cross-platform comparison across six nanocarrier systems and explicit stratification of evidence by translational stage.

Methods

A structured narrative review was conducted using OVID MEDLINE, Embase, Scopus, Web of Science, and PubMed from database inception to September 2025, supplemented by citation chaining and targeted Google Scholar searches. Data extraction focused on carrier architecture, drug-loading and release characteristics, delivery routes, mechanistic behaviour, therapeutic outcomes, and safety profiles. This review was conducted in accordance with the general principles for narrative reviews as described in the Scale for the Assessment of Narrative Review Articles (SANRA).

Results

Key nanocarrier classes included liposomes, polymeric micelles, dendrimers, nanosuspensions, nanoemulsions, and chitosan- and protein-based nanoparticles. Compared with conventional formulations, these systems demonstrated improved corneal residence, enhanced mucoadhesion, increased transscleral diffusion, reduced dosing frequency, and sustained intraocular exposure. Clinically translated examples include cyclosporine A nanomicelle and nanoemulsion formulations, marketed as Cequa (0.09%), Restasis (0.05%), and Ikervis (0.1%), approved for dry eye disease, and a subconjunctival PLGA nanoparticle depot that achieved greater than 20% intraocular pressure reduction sustained over 90 days from a single injection in early clinical evaluation. Applications spanned anterior-segment disorders, including dry eye disease, conjunctivitis, infectious keratitis, ocular inflammation, and glaucoma, and posterior-segment diseases such as diabetic retinopathy, age-related macular degeneration, retinoblastoma, and retinopathy of prematurity.

Conclusion

Lipid-based and polymeric nanocarrier platforms are currently closest to clinical translation, with approved formulations and early-phase trial data supporting meaningful therapeutic advantages over conventional delivery. Realising the full potential of ocular nanomedicine will require addressing residual challenges in long-term ocular safety, manufacturing scalability, and regulatory compliance, particularly for posterior-segment applications, where non-invasive topical delivery remains largely at the preclinical stage.

Introduction

Nanotechnology has emerged over the past two decades as a transformative force in medicine, capitalising on the unique physicochemical properties of materials at the nanometer scale.¹ In the realm of drug delivery, nanomedicine has fundamentally changed how therapeutics, ranging from small-molecule chemotherapeutics to large biologics, can be transported and released within the body.² By enabling drugs to be targeted to specific tissues and cellular receptors, nanoparticle-based carriers can improve treatment efficacy while minimising off-target side effects.³ This promise is particularly compelling in ophthalmology, where conventional treatments face significant anatomical and physiological hurdles.⁴ For anterior-segment delivery, topical eye drops lose approximately 75% of the instilled dose to nasolacrimal drainage within seconds; the stratified corneal epithelium, reinforced by tight junctions and an overlying mucus layer, limits transcorneal absorption to less than 5% of the applied dose, with precorneal drug residence typically under two minutes owing to a tear turnover rate of approximately 1 µL per minute. Posterior-segment delivery presents an additional tier of challenge: the blood-aqueous and blood-retinal barriers restrict systemic drug entry, while the vitreous body and retinal pigment epithelium impede transscleral diffusion and intravitreal drug distribution to the retina.⁵ These limitations in current ocular therapy underscore the need for more advanced delivery strategies.

Nanoscale drug carriers offer a promising alternative approach for treating eye diseases. By virtue of their small size and modifiable surfaces, nanoparticles can be engineered to penetrate into ocular tissues, provide sustained drug release, and even selectively target cells or molecular receptors in the eye.⁵ A wide spectrum of nanotechnologies is being explored in this context, including liposomes, dendrimers, polymeric micelles, nanoemulsions, nanosuspensions of drug nanocrystals, and newer systems like chitosan-based or protein-based nanoparticles.⁶ Despite this expanding evidence base, existing narrative reviews have largely examined individual nanocarrier classes without integrating cross-platform comparisons, stratifying evidence by translational stage, or providing a unified assessment spanning both anterior- and posterior-segment disease applications, limitations that reduce their utility for clinicians and translational researchers seeking to contextualise platform-specific advances within the broader therapeutic landscape. Unlike prior reviews that focus predominantly on single nanocarrier classes or isolated disease applications, this review provides an integrated, cross-platform comparison spanning both anterior- and posterior-segment diseases, and contextualising findings within a translational and regulatory framework. In this review, we describe these nanocarrier platforms and how their structural features influence ocular drug loading and delivery. Subsequently, the application of nanotechnology to major ophthalmic disorders is also discussed, highlighting both well-established and emerging approaches. Novel strategies at the interface of nanotechnology with gene therapy and neuroprotection are also examined. Importantly, the review critically appraises nanocarrier limitations, including cytotoxicity concerns, formulation instability, manufacturing scalability, and regulatory hurdles, alongside their potential advantages, to provide a balanced assessment of translational feasibility. Finally, current challenges in translating ocular nanomedicine to clinical use and future directions for this rapidly evolving field are considered.

Methods

A comprehensive literature search was performed in OVID MEDLINE, Embase, Scopus, Web of Science Core Collection, and PubMed from database inception to September 2025. Search strategies combined controlled vocabulary (eg, MeSH and Emtree terms) and free-text keywords relating to nanotechnology and ophthalmic therapy. Search strings were adapted for each database and limited to English-language publications; no geographic restrictions were applied. Articles were considered eligible if they: (i) described the design, physicochemical properties, or pharmacokinetic behaviour of ocular nanocarrier systems; (ii) evaluated drug-loading strategies, release characteristics, or transport mechanisms relevant to ocular tissues; or (iii) reported preclinical, translational, or clinical application of nanotechnology in the management of major anterior- or posterior-segment ophthalmic diseases. Full-text articles that met the inclusion criteria were examined to extract information on nanocarrier platform type, structural and surface characteristics, drug class and release behaviour, delivery route, ocular penetration strategy, pharmacologic or biological mechanism, evidence model (preclinical or clinical), key therapeutic outcomes, and safety or tolerability signals. This review was conducted in accordance with the general principles for narrative reviews as described in the Scale for the Assessment of Narrative Review Articles (SANRA). Evidence was synthesised thematically by nanocarrier platform and disease category and explicitly stratified by translational stage (in vitro, preclinical in vivo, or clinical) to support interpretability and avoid overstatement of preclinical findings.

Nanoparticle Types and Systems for Ocular Drug Delivery

Liposomes

Liposomes are lipid vesicles composed of phospholipid bilayers enclosing an aqueous core, which allows them to carry both hydrophilic drugs in the core and hydrophobic drugs in the bilayer.⁷ For ophthalmic delivery, cationic liposomes are particularly effective: their positively charged surface adheres to the negatively charged corneal epithelium and mucous layer, prolonging drug residence on the eye.⁸ Conversely, “stealth” liposomes coated with neutral hydrophilic polymers, such as polyethylene glycol (PEG), are less adhesive but avoid rapid clearance, giving them more time to penetrate tissues.⁹ Various surface modifications, for example, attaching mucoadhesive polymers or targeting ligands, have been used to further enhance liposome retention and specificity in ocular delivery.⁷ Upon administration, liposomes can fuse with cell membranes or be endocytosed by cells, releasing their drug payload into ocular tissues. Owing to their biocompatibility and versatility, liposomes represent one of the most extensively studied nanoparticle systems in ophthalmology. Nevertheless, limitations persist, including physical instability and drug leakage during storage, relatively low encapsulation efficiency for certain lipophilic payloads, and stringent sterilisation requirements that add manufacturing complexity and cost.^7–9

Dendrimers

Dendrimers are highly branched polymeric nanoparticles, only a few nanometers in diameter. They possess a multitude of reactive surface groups - for example, the numerous amine termini of a PAMAM dendrimer, and interior voids, allowing drugs to be attached to their surface or encapsulated in their core structure.¹⁰ The dense cationic surface of many dendrimers also promotes uptake into cells, a feature that has been used to deliver genetic therapies to ocular tissues. However, unmodified polycationic dendrimers can disrupt cell membranes and induce cytotoxicity at higher concentrations.¹¹ To improve safety, dendrimer surfaces are often neutralised by attaching hydrophilic polymers like PEG or acetyl groups, and some dendrimers are synthesised with biodegradable linkages so that they break down into excretable fragments.¹² With their high loading capacity and adaptable chemistry, well-designed dendrimers are promising vehicles for ocular drug and gene delivery.

Polymeric Micelles

Nanomicelles are self-assembled nanoparticles formed by amphiphilic surfactants or block copolymers. Above a threshold concentration in solution, these amphiphiles cluster into nanoscale micelles, which are 10–100 nm in diameter, with a hydrophobic core that solubilises poorly water-soluble drugs and a hydrophilic shell that stabilises the structure.¹³ Their small size allows them to penetrate ocular tissues and improve the delivery of drugs that would otherwise have low solubility. Micelles can also be engineered to release drugs in response to environmental triggers, such as pH or redox changes, enabling drug release only under specific conditions, for example, in inflamed tissues.¹⁴ A practical limitation is that the tear film can dilute and destabilise conventional micelles, causing premature drug loss. To address this, researchers use polymers with an ultra-low critical micelle concentration or chemically cross-link the micelle structure to keep it intact longer on the eye, achieving more sustained drug release and therapeutic effect.¹⁵

Nanosuspensions

A nanosuspension is a colloidal dispersion of insoluble drug nanocrystals in an aqueous medium, stabilised by surfactants or polymers to prevent clumping. Converting a hydrophobic drug into nanometer-sized crystals vastly increases its surface area and dissolution rate, leading to improved corneal penetration and bioavailability.¹⁶ This approach enables high-dose eye drop formulations of drugs that would otherwise require oily solvents or irritating co-solvents. For instance, a nanosuspension of cyclosporine A for dry eye delivered higher drug concentrations to the tear film with less irritation than the conventional oily cyclosporine formulation.¹⁷ Drug nanocrystals also adhere to the mucin layer on the eye’s surface and dissolve gradually, producing a sustained-release effect at the site of application. To maintain stability, nanosuspensions rely on appropriate surface charges and steric stabilisers: a mildly positive particle charge promotes adhesion to the ocular surface, whereas excessive cationic charge causes binding by tear proteins and accelerates clearance.¹⁸ With careful formulation, stable nanosuspension eye drops have been achieved for multiple drugs.

Nanoemulsions

Nanoemulsions are minute oil-in-water emulsions in which drug-containing oil droplets, typically 20–200 nm in diameter, are finely dispersed in an aqueous phase and stabilised by surfactants.¹⁹ Their tiny droplets can spread uniformly over the eye and penetrate the tear film and corneal epithelium more effectively than larger emulsion drops, leading to improved drug absorption. Cationic nanoemulsions, formulated with positively charged lipids or polymer emulsifiers, adhere strongly to the negatively charged ocular surface mucins, substantially prolonging the contact time of the drug-loaded droplets.²⁰ This principle is used in cyclosporine emulsions for dry eye therapy to enhance drug retention on the eye.²¹ When optimally formulated, nanoemulsions can significantly increase ocular drug exposure and reduce the frequency of dosing needed relative to conventional eye drops. However, surfactant-related ocular irritation, potential for long-term epithelial toxicity, and physical instability upon storage remain important formulation challenges that must be addressed before broad clinical adoption.^21,22

Chitosan Nanoparticles

Chitosan is a cationic polysaccharide derived from chitin that exhibits excellent mucoadhesive and biocompatible properties.²² Nanoparticles made from chitosan inherently carry a positive surface charge, which confers two key advantages: strong electrostatic binding to the negatively charged mucin layer of the tear film, anchoring the particles on the eye, and a transient loosening of tight junctions between corneal epithelial cells, enhancing paracellular drug penetration.²² Drugs entrapped in chitosan nanoparticles are released gradually as the polymer swells and biodegrades, enabling sustained delivery that can be tuned from hours to days by adjusting cross-linking and formulation parameters.²³ Importantly, chitosan and its breakdown products are generally non-toxic to ocular tissues; in fact, chitosan is already used as a component in certain tear-replacement eye drops, underscoring its safety in ophthalmic applications.²⁴ With their combination of mucoadhesion, penetration enhancement, and controlled release, chitosan-based nanoparticles represent a robust platform for ophthalmic drug delivery. That said, batch-to-batch variability in molecular weight and degree of deacetylation, limited regulatory precedent for chitosan-based injectables, and questions around long-term corneal tolerability at higher concentrations remain challenges for clinical-scale development.²⁴

Protein Nanoparticles

Natural proteins such as albumin, gelatin, and casein have been used to construct nanoparticle carriers for ocular therapy. Protein nanoparticles are biodegradable and often inherently non-toxic, and certain proteins can target specific tissues via receptor interactions.²⁵ In ocular applications, albumin nanoparticles have been tested for delivering anti-VEGF antibodies and corticosteroids to the retina, taking advantage of albumin’s binding to receptors, such as gp60 and SPARC, on retinal blood vessels to enhance drug accumulation in the target site.²⁶ Other protein nanoparticles derived from gelatin (collagen) or milk casein have likewise shown good biocompatibility in eye models.²⁵ By leveraging natural molecules, protein-based nanoparticles offer a promising and well-tolerated platform for drug delivery in the eye. Key limitations include the risk of immunogenic responses to exogenous proteins, susceptibility to proteolytic degradation, and variability in protein source quality that can complicate manufacturing consistency and regulatory approval.^25,26

A consolidated summary of the major nanocarrier platforms discussed in this section, including their physicochemical features, delivery strategies, advantages, and limitations, is presented in Table 1, while the relationship between nanocarrier platforms, routes of ocular administration, and their major anterior- and posterior-segment therapeutic applications is summarised schematically in Figure 1.

Table 1.

Structural Features, Delivery Routes, and Therapeutic Advantages and Limitations of Nanocarrier Systems in Ocular Drug Delivery

Platform	Physicochemical Profile (Size; Zeta Potential; Drug Loading)	Drug Class and Release Characteristics	Delivery Route and Ocular Penetration Strategy	Benefits	Limitations	References
Liposomes	Phospholipid bilayer vesicles with aqueous core; ~50–300 nm; neutral to mildly negative; zeta potential: −5 to −30 mV (anionic) or +20 to +40 mV (cationic); encapsulation efficiency 60–90%	Encapsulate hydrophilic and lipophilic agents; passive/active loading; diffusion-mediated and composition-dependent release	Topical, periocular, intravitreal; surface mucoadhesion prolongs effect	Biocompatible; dual-payload capacity; several clinically validated formulations.	Low drug loading, stability and leakage issues, sterilization challenges.	[4,7]
Dendrimers	Precisely branched macromolecules (2–20 nm); tunable end-group charge; zeta potential: +10 to +40 mV (unmodified PAMAM), near neutral when PEGylated; drug loading: 2–20% w/w	Encapsulation or covalent conjugation; diffusion or linker cleavage release	Topical, intraocular, systemic retinal targeting	High payload density; selective uptake by inflammatory cells	High cost and synthesis complexity; cationic toxicity concerns	[10,12]
Polymeric nanoparticles	Biodegradable polymer cores; 10–200 nm; tunable surface charge; zeta potential: −10 to −40 mV (PLGA); drug loading: 5–30% w/w (EE 50–90%).	Small molecules to biologics; diffusion + polymer degradation yield sustained release.	Topical, periocular, intravitreal; cationic/PEG coatings aid mucoadhesion and transport.	Tailorable kinetics; protects cargo; supports targeted delivery.	Possible cytotoxic by-products; scale-up complexity; burst release risk.	[14,27]
Polymeric micelles	Amphiphilic block-copolymer core–shell nanostructures; 10–100 nm; zeta potential: −5 to −20 mV; drug loading: 5–25% w/w.	Hydrophobic-core solubilization; release via diffusion or micelle dissociation.	Topical; PEG shells reduce clearance and improve stability.	Improves solubility; reduced irritation; sustained delivery potential.	Dilution-induced dissociation; limited hydrophilic drug capacity.	[13,27]
Nanosuspensions	Stabilized drug nanocrystals; ~200–600 nm; zeta potential: ±20 to ±40 mV (stability threshold); drug loading: ~100% (pure drug nanocrystals; no carrier dilution).	Dissolution-controlled release with high surface area.	Topical suspensions; direct nanoparticle bioavailability.	Very high loading; simple compositions; avoids carrier toxicity.	Physical instability/Ostwald ripening; limited to hydrophobic APIs.	[16,18]
Nanoemulsions	Oil-in-water droplets (20–500 nm); mildly negative or cationic with surfactants; zeta potential: −20 to −40 mV (anionic) or +20 to +40 mV (cationic); drug loading: 0.5–5% w/v.	Lipophilic drugs dissolved in oil; gradual release as droplets interact with tear film.	Topical drops; cationic systems adhere to negatively charged ocular surface.	Enhanced residence and bioavailability; scalable manufacture.	Surfactant-related irritation; physical instability over time.	[19,20]

Abbreviations: Nm, nanometer(s); PEG, polyethylene glycol; PLGA, poly(lactic-co-glycolic acid); API, active pharmaceutical ingredient; SLN, solid lipid nanoparticle; NLC, nanostructured lipid carrier.

Figure 1.

Nanocarrier platforms, routes of ocular administration, and major anterior- and posterior-segment therapeutic applications. (Created in BioRender. Singh, R. (2026) https://BioRender.com/pfye2lf; publication rights held by the authors).

Application of Nanotechnologies in Ocular Diseases

Dry Eye Disease (DED)

Dry eye is a multifactorial condition characterised by tear film insufficiency or instability, resulting in hyperosmolarity and inflammation of the ocular surface.²⁸ Conventional management, including artificial tears, lubricating ointments, and anti-inflammatory eye drops such as cyclosporine, often provides only transient relief because topically applied agents are rapidly diluted and cleared. Nanotechnology offers ways to improve drug retention and efficacy in DED. A variety of nanoparticle formulations, including liposomes, nanoemulsions, nanosuspensions, and polymeric micelles, have been investigated to enhance therapeutic efficacy. Liposomal eye drops encapsulating immunosuppressants like cyclosporine A, for example, achieved higher tear-film drug levels and less ocular irritation compared to the standard cyclosporine emulsion drop.²⁹ Similarly, cyclosporine and vitamin A nanosuspensions have demonstrated improved corneal drug bioavailability with minimal irritation, eliminating the need for harsh solvents.²⁹ Cationic nanoemulsions, such as the formulation used in a commercially available cyclosporine eye drop, prolong drug residence on the eye by binding to the negatively charged ocular surface, while polymeric nanomicelles provide sustained release of anti-inflammatory drugs on the eye.³⁰ Collectively, these nanotechnologies significantly enhance drug delivery in dry eye, resulting in greater tear production and reduced inflammatory damage in preclinical models.

Conjunctivitis

Inflammation or infection of the conjunctiva, also known as pink eye, is another condition where sustained ocular drug delivery would improve treatment outcomes.³¹ Biodegradable polymer nanoparticles have been developed that slowly release anti-inflammatories or antibiotics on the conjunctival mucosal surface. For example, a PEG-PLGA nanoparticle formulation of dexibuprofen provided extended drug release and ameliorated inflammation in an experimental model of conjunctivitis.³² Similarly, tacrolimus encapsulated in polymer nanocapsules showed prolonged release with minimal toxicity, suggesting a potential steroid-sparing nanotherapy for chronic inflammatory conjunctivitis.³³ In addition, novel ophthalmic inserts made of nanofibers are being developed to treat conjunctival infections. A cross-linked nanofiber insert loaded with ofloxacin could be placed in the inferior fornix of the eye, where it continuously released therapeutic levels of the drug for up to four days.³² Such sustained-release inserts could dramatically reduce dosing frequency and improve patient compliance in bacterial conjunctivitis compared to the typical regimen of hourly or multiple daily eye drops.

Infectious Keratitis

Infections of the cornea require high and sustained drug levels at the infection site, which is difficult to achieve with ordinary eye drops. Several nanotechnology-based strategies are in development to treat bacterial or fungal keratitis more effectively. One strategy is to encapsulate antimicrobial agents in lipid or polymer nanoparticles to improve corneal penetration and retention. A natamycin-loaded solid lipid nanoparticle formulation developed for fungal keratitis provided prolonged drug release and achieved higher antifungal efficacy in the cornea than the conventional natamycin suspension.³⁴ Nanofiber scaffold patches have also been tested: a propolis-embedded nanofiber mat, incorporating an antimicrobial resin and even mesenchymal stem cells, was shown to adhere to the cornea and promote healing in an experimental keratitis model.³⁵ These examples illustrate how nanotechnologies can maintain high drug levels on the corneal surface and potentially improve outcomes in severe keratitis while reducing the need for frequent drop administration.

Glaucoma and Optic Neuropathies

Glaucoma is a progressive optic neuropathy characterised by elevated intraocular pressure (IOP) and degeneration of retinal ganglion cells (RGCs), leading to optic nerve damage.³⁶ The mainstay of glaucoma therapy is lowering IOP, typically with topical eye drops, but conventional drops often have limited absorption and require frequent use. Nanotechnology-based formulations of glaucoma medications have shown markedly improved outcomes in preclinical studies. A range of drugs, including timolol, brimonidine, latanoprost, and others, have been encapsulated in liposomes, dendrimers, solid lipid nanoparticles, and micellar or nanoemulsion droplets, yielding greater IOP reduction and longer-lasting effects compared to conventional eye drops.⁵ Another example is that of a positively charged silica nanoparticle carrying brimonidine that was designed to adhere to the ocular surface; it extended the drug’s pressure-lowering effect to nearly 12 hours, versus about 2 hours for a standard brimonidine drop.³⁷ Nanoparticles have also been used to deliver combinations of glaucoma drugs and novel agents: a biodegradable dendrimer-derived nanoparticle loaded with two glaucoma drugs provided sustained, zero-order drug release and significantly enhanced penetration into ocular tissues, resulting in prolonged IOP control in an animal model.³⁸

Nanotechnology is also being applied to protect retinal ganglion cells (RGCs) and optic nerve fibres from glaucomatous damage. Several neuroprotective or antioxidant compounds that could benefit RGCs, such as curcumin, catechins from green tea, or thymoquinone from Nigella sativa, are being formulated into nanoparticles to enhance their delivery to the retina.³⁹ Even for optic neuropathies unrelated to glaucoma, for example, optic nerve injury from ischemia or trauma, sustained-release nanoparticle therapies are being explored. One study found that injecting biodegradable microspheres releasing an anti-inflammatory drug, ketorolac, around the injured optic nerve delayed RGC death after nerve crush more effectively than standard eye drop treatment.⁴⁰ Other researchers have developed liposome-based vectors to co-deliver growth factors and signalling peptides to retinal cells, significantly promoting RGC survival and even axon regeneration in optic nerve injury models.⁴¹ Though such neuroprotective approaches are still experimental, they highlight nanotechnology’s potential not just to lower IOP but also to directly safeguard neurons in optic neuropathies.

Ocular Inflammation

In conditions like anterior uveitis or post-surgical inflammation, patients are commonly treated with intensive courses of corticosteroid or NSAID eye drops, which can have significant side effects and may not penetrate well into deeper ocular tissues.⁴² Nanocarriers have been developed to improve drug localisation and potency for ocular inflammation. For instance, indomethacin-loaded lipid nanoparticles coated with chitosan exhibited superior penetration into the cornea and anterior segment than uncoated nanoparticles, allowing more effective delivery of the anti-inflammatory drug to target tissues.²³ In addition, nanocarriers enable the ocular use of natural anti-inflammatory compounds that would otherwise be impractical. Curcumin, catechins, resveratrol and other plant-derived antioxidants have very poor water solubility and are rapidly cleared from the eye, but when encapsulated in polymeric nanoparticles or nanoemulsions, they achieve much higher ocular bioavailability and efficacy.³⁷ Nanoparticle-delivered curcumin, for example, suppressed inflammatory markers on the ocular surface more effectively than curcumin eye drops in experimental models.⁴³ These findings illustrate that nanotechnology can both improve conventional anti-inflammatory drugs and revive interest in nutraceutical or herbal therapies for ocular inflammation.

Diabetic Retinopathy (DR)

DR is a microvascular retinal disease in diabetes, marked by a non-proliferative stage, with microaneurysms and haemorrhages, that can progress to a proliferative stage with retinal neovascularisation.⁴⁴ Current treatments for sight-threatening DR include panretinal laser photocoagulation and repeated intravitreal anti-VEGF injections to regress neovascular vessels, but laser can compromise peripheral vision, and frequent intraocular injections pose risks and burdens.⁴⁴ Nanotechnology-based approaches are being investigated to provide less invasive, sustained treatments for DR. For instance, lipid or polymer nanoparticles are being studied to deliver anti-VEGF therapy to the retina from eye drops or long-acting injectable formulations, to reduce or replace the need for monthly intravitreal injections.⁴⁵ Nanocarriers might also deliver neuroprotective factors to address the retinal neurodegeneration that accompanies DR. Studies in diabetic animal models have shown that factors like somatostatin, which inhibits excitotoxic damage, or brain-derived neurotrophic factor (BDNF) can prevent retinal neuron loss; encapsulating such peptides in nanoparticles could allow them to be released in a sustained fashion to the diabetic retina.⁴⁶ By combining anti-VEGF effects with neuroprotective therapy in a single platform, nanotechnology may help treat both the vascular and neural components of DR more effectively than current methods.

Age-Related Macular Degeneration (AMD)

AMD, a leading cause of blindness in the elderly, involves degeneration of the macula. Advanced AMD is classified into dry (atrophic) and wet (neovascular) forms.⁴⁷ Wet AMD is treated with intravitreal anti-VEGF injections that can slow or arrest neovascular growth but require frequent (monthly or bimonthly) dosing and carry risks like intraocular infection and cataract.⁴⁷ Nanotechnology-based delivery systems aim to provide less invasive and longer-acting therapies for AMD. Lipid nanoparticles such as liposomes have been explored as carriers for both drugs and genes in AMD therapy. In one study, bevacizumab encapsulated in liposomes demonstrated sustained release with preserved bioactivity, and suitably small liposomes applied as eye drops or periocular injections were able to reach the retina in experimental models.⁴⁸ Polymeric nanocarriers like PLGA nanoparticles and polymeric micelles have similarly achieved extended intraocular delivery of anti-angiogenic agents. A single intravitreal injection of PLGA nanoparticles loaded with axitinib, a small-molecule VEGF inhibitor, significantly suppressed choroidal neovascularisation in a model of wet AMD, due to prolonged drug release.⁴⁹ Nanocarriers have also been used to deliver genetic therapies: an intravitreal nanoemulsion carrying an anti-VEGF antisense oligonucleotide produced much greater inhibition of choroidal neovascular growth in mice than the free oligonucleotide, owing to improved cellular uptake and retention.⁵⁰ While these strategies are still under development, they exemplify how nanotechnology might fundamentally improve AMD management by making treatments more targeted and durable.

Retinoblastoma

Retinoblastoma is a pediatric retinal malignancy caused by mutations in the RB1 tumour-suppressor gene. It is typically treated with systemic or intra-arterial chemotherapy and focal treatments, laser or cryotherapy, with enucleation reserved for advanced cases.⁵¹ Nanotechnology is being harnessed to concentrate chemotherapeutic agents within the eye and minimise systemic exposure in retinoblastoma therapy. Polymer nanoparticles, for instance, can be loaded with standard chemotherapy drugs, a periocular injection of carboplatin-loaded polymethylmethacrylate nanoparticles achieved 3–4-fold higher intraocular carboplatin levels than a conventional periocular carboplatin injection.⁵² Targeted nanoparticles have further improved delivery: folate-conjugated silica nanoparticles carrying topotecan selectively accumulated in retinoblastoma cells and produced greater tumour control compared to non-targeted nanoparticles.⁵³ In animal models, lactoferrin-coated nanoparticles loaded with carboplatin or etoposide prolonged the drugs’ half-life in the eye and increased tumour drug uptake, while the lactoferrin itself provided a complementary anti-tumour effect.⁵⁴ Furthermore, nanoparticle-mediated gene therapy strategies are under exploration. One approach used gold nanoparticles to deliver a peptide that inhibits the oncogenic MDM2 protein, thereby reactivating the tumour’s own p53 tumour-suppressor pathway and triggering cancer cell apoptosis.⁵⁵ These technologies remain in the research stage; they suggest that nanotechnology could eventually enable more potent and less invasive treatments for retinoblastoma.

Retinopathy of Prematurity (ROP)

ROP is a proliferative retinal vascular disease in premature infants, driven by abnormal blood vessel growth in the retina that can lead to retinal detachment. Standard ROP treatments involve ablating the peripheral avascular retina with laser or injecting anti-VEGF agents intravitreally, both of which have significant risks in infants, such as anaesthesia complications or developmental side effects.⁵⁶ Researchers are exploring systemic or periocular nanoparticle delivery of anti-angiogenic drugs, which might treat both eyes without direct intraocular injections. In neonatal animal models, certain surface-modified nanoparticles have been shown to cross the blood-retinal barrier, suggesting that intravenous injection of drug-loaded nanoparticles could reach the retina. Gold nanoparticles can bind excess VEGF or its receptors, inhibiting their signalling; in a rat model of oxygen-induced retinopathy, gold nanoparticles significantly reduced pathological neovascularisation.⁵⁷ Cerium oxide nanoparticles (nanoceria), acting as catalytic antioxidants, have been shown to reduce reactive oxygen species and attenuate aberrant retinal neovascular growth. Nanoparticles have also been used to deliver biological angiogenesis inhibitors, such as a plasminogen-derived peptide, in ROP models, resulting in marked suppression of abnormal retinal vessel proliferation.⁵⁸ These nanotechnologies offer a compelling vision of ROP treatment that avoids surgical lasers or intraocular injections while protecting the delicate, developing retina.

These anterior and posterior segment disease applications, along with their associated nanocarrier platforms, delivery routes, evidence context, outcomes, and safety considerations, are summarised in Table 2.

Table 2.

Applications of Ocular Nanocarrier Systems Across Major Anterior and Posterior Segment Diseases

Indication	Clinical Objective and Mechanism	Nanocarrier and Payload	Route and Regimen	Study Model/Evidence	Key Outcomes	Safety and Tolerability	References
Dry Eye Disease	Reduce T-cell-mediated surface inflammation; increase tear production via calcineurin inhibition	Nanomicelles containing cyclosporine A 0.09%	Topical drops, BID	Clinical- Phase 3 randomised controlled trial (RCT)	Significant improvement in Schirmer score vs vehicle	Mild transient irritation; minimal systemic exposure	[29,59]
Conjunctivitis/ocular surface inflammation	Provide sustained anti-inflammatory or antimicrobial drug exposure on the conjunctival surface to reduce inflammation and infection	Biodegradable PEG-PLGA nanoparticles with dexibuprofen; polymer nanocapsules with tacrolimus; antibiotic-loaded nanofiber inserts	Topical eye drops; conjunctival insert placed in inferior fornix	Preclinical (in vivo)—inflammatory conjunctivitis and anti-infective animal models	Reduced inflammatory signs and improved therapeutic effect vs conventional drops; inserts maintained drug levels for up to 4 days	Minimal toxicity reported in experimental studies; biodegradable formulations	[32]
Infectious keratitis	Increase antimicrobial exposure within the cornea and enhance drug residence to support more effective pathogen clearance	Polymeric and lipid-based nanoparticles and nanoemulsions loaded with Natamycin	Topical eye drops; some formulations evaluated as adjunct periocular delivery	Preclinical (in vivo)—bacterial and fungal keratitis animal models	Reduced microbial load, faster lesion resolution, and improved clinical scores versus conventional formulations in experimental models	Generally well tolerated in animal studies; no major corneal toxicity reported	[34]
Glaucoma/Ocular Hypertension	Lower IOP by enhancing uveoscleral outflow through sustained prostaglandin release	PLGA nanoparticle depot with latanoprost	Subconjunctival, single injection	Clinical (early-phase) + Preclinical (in vivo)—single subconjunctival injection depot trial; corroborated by animal data	>20% IOP reduction for 90 days	Well tolerated; no major injection-site toxicity	[38,40]
Diabetic Retinopathy	Suppress VEGF-driven retinal neovascularization	Chitosan-coated PLGA nanoparticles with bevacizumab	Subconjunctival periocular injection	Preclinical (in vivo)—streptozotocin rat diabetic retinopathy model	VEGF reduced and neovascularization inhibited	No local tissue toxicity reported	[45]
Age Related Macular Degeneration	Target inflammatory microglia and reduce CNV and leakage	Dendrimer-drug conjugate with triamcinolone	Systemic IV dosing	Preclinical (in vivo)—laser-induced choroidal neovascularisation mouse model	>80% CNV reduction vs minimal effect with free drug	No systemic toxicity observed at effective dose	[49]
Retinoblastoma	Enhance intraocular delivery of chemotherapeutic and targeted agents to improve tumor control while reducing systemic toxicity	Polymeric, lipid and inorganic nanoparticles; drug-loaded mesoporous silica and gold-based platforms; nanoformulations incorporating agents such as carboplatin, topotecan, doxorubicin, and natural-product derivatives	Intravitreal, periocular/subconjunctival, and experimental targeted local delivery systems	Preclinical (in vitro + in vivo)—retinoblastoma cell lines and xenograft animal tumour models	Improved intratumoral drug exposure, reduced tumor burden, enhanced cytotoxic response or photodynamic synergy compared with free-drug formulations in experimental studies	Favourable tolerability in reported preclinical models; systemic exposure lower than with conventional delivery	[52]
Retinopathy of prematurity (ROP)/neovascular retinopathy	Mitigate oxidative-stress driven VEGF up-regulation and pathological retinal neovascularization to preserve retinal structure	Antioxidant and anti-angiogenic nanomaterials, including cerium oxide (CeO2) nanoparticles	Primarily intravitreal administration in experimental models	Preclinical (in vivo)—oxygen-induced retinopathy and oxidative-injury neonatal animal models	Reduced VEGF protein levels, fewer neovascular tufts, and attenuation of abnormal vascular sprouting in experimental settings	Reported as well tolerated in animal models at tested doses	[58]

Abbreviations: DED, Dry eye disease; IK, Infectious keratitis; ROP, Retinopathy of prematurity; DR, Diabetic retinopathy; AMD, Age-related macular degeneration; CNV, Choroidal neovascularisation; DME, Diabetic macular edema; IOP, Intraocular pressure; NP, Nanoparticle; PLGA, Poly(lactic-co-glycolic acid); PEG, Polyethylene glycol; SLN, Solid lipid nanoparticle; NLC, Nanostructured lipid carrier; CsA, Cyclosporine A; VEGF, Vascular endothelial growth factor; ROCK, Rho-associated protein kinase.

Table 3 summarises marketed and regulatory-approved nano-based ophthalmic formulations, comparing their nanocarrier platforms, indications, and key advantages over conventional alternatives. These approved products demonstrate that lipid-based nanocarriers and biodegradable polymer systems have successfully bridged the translational gap, and serve as benchmarks against which investigational nanocarrier platforms should be evaluated.

Table 3.

Marketed and Approved Nano-Based Ophthalmic Formulations and Their Advantages Over Conventional Comparators

Product (Brand/Sponsor)	Active Ingredient	Nanocarrier Platform	Indication	Regulatory Status	Key Points
Restasis (Allergan/AbbVie)60	Cyclosporine A 0.05%	Nanoemulsion (oil-in-water)	Dry eye disease	FDA approved 2002	Improved corneal retention vs oily CsA solutions; reduced burning on instillation; well-established long-term safety profile60,61
Cequa (Sun Pharma)	Cyclosporine A 0.09%	Nanomicelles (OcuSorb technology)	Dry eye disease	FDA approved 2018	Higher drug concentration achievable in aqueous vehicle; superior corneal bioavailability vs emulsion; preservative-free62
Ikervis (Santen)	Cyclosporine A 0.1%	Cationic nanoemulsion	Severe dry eye disease (adults)	EMA approved 2015	Cationic charge prolongs electrostatic adhesion to anionic corneal mucins; once-daily dosing; steroid-sparing63,64
Verkazia (Santen)	Cyclosporine A 0.1%	Cationic nanoemulsion	Vernal keratoconjunctivitis (paediatric)	FDA approved 2021	First approved long-term pharmacological treatment for VKC; avoids corticosteroid-related adverse effects (cataract, IOP rise)64
Xelpros (Sun Pharma)	Latanoprost 0.005%	Nanoemulsion	Glaucoma/ocular hypertension	FDA approved 2018	Preservative-free formulation; reduced ocular surface toxicity vs BAK-preserved latanoprost; improved tolerability for long-term use65
Ozurdex (Allergan/AbbVie)	Dexamethasone 0.7 mg	Biodegradable PLGA intravitreal implant	Macular oedema (RVO, DME), non-infectious uveitis	FDA approved 2009 (RVO/uveitis); 2014 (DME)	3–6 month sustained release from a single intravitreal injection; substantially reduces injection frequency vs monthly triamcinolone; biodegradable (no implant removal required)66,67

Abbreviations: BAK, benzalkonium chloride; CsA, cyclosporine A; DME, diabetic macular oedema; EMA, European Medicines Agency; FDA, US Food and Drug Administration; IOP, intraocular pressure; PLGA, poly(lactic-co-glycolic acid); RVO, retinal vein occlusion; VKC, vernal keratoconjunctivitis.

Future Directions

Future advances in ocular nanotherapy are expected to increasingly emphasise precision targeting, stimuli-responsive delivery, and disease-specific therapeutic modulation. Emerging “smart” nanocarriers are being engineered to release their payload selectively within diseased ocular tissues in response to local biochemical cues such as altered pH, enzymatic activity, oxidative stress, or inflammatory mediators. Refinement of surface ligands, charge characteristics, and environment-sensitive materials may enable nanoparticles to preferentially accumulate in affected cells or tissue compartments while minimising off-target exposure and adverse effects. Parallel advances in materials science are driving the development of next-generation nanocarriers that are fully biodegradable, non-immunogenic, and suitable for chronic or repeated administration, addressing key safety concerns that currently limit long-term ocular use.^37–58,68

Over the next five years, meaningful progress in ocular nanotherapeutics must shift from proof-of-concept innovation toward robust clinical translation. This transition will require greater reliance on reproducible preclinical models that more accurately replicate human ocular anatomy, pharmacokinetics, and disease chronicity, coupled with standardised reporting of biodistribution, durability, and long-term safety. Equally critical will be the early integration of regulatory considerations, including scalable manufacturing, sterility assurance, formulation stability, and quality control. Early-phase clinical trials should prioritise clinically relevant endpoints such as sustained efficacy, reduced treatment burden, improved adherence, or safety advantages over existing delivery platforms, rather than surrogate pharmacodynamic outcomes alone. Achieving these goals will necessitate close collaboration between clinicians, formulation scientists, industry stakeholders, and regulatory authorities to identify indications in which nanocarrier systems offer a clear and realistic advantage over conventional therapies.

Nanotechnology is also poised to converge with gene therapy and regenerative medicine, opening new therapeutic avenues in ophthalmology. Nanoparticles may serve as non-viral vectors for gene editing or gene silencing, facilitating targeted correction of genetic retinal disorders while avoiding the immunogenicity and payload limitations of viral systems. They may additionally enhance cell-based therapies by delivering neurotrophic or pro-survival factors that support the survival, integration, and function of transplanted retinal or optic nerve cells.⁶⁹ As precision medicine evolves, nanotherapies could be increasingly tailored to individual genetic or molecular disease profiles, while nanoparticle-based contrast agents combined with advanced ocular imaging may enable real-time monitoring of drug distribution and therapeutic response.⁶

Despite these promising directions, nanotechnology should not be portrayed as a universal solution to the challenges of ocular drug delivery. Expectations of routine non-invasive topical delivery to the posterior segment, wholesale replacement of intravitreal injections, or broad neuroregeneration remain largely unsubstantiated and risk overstating current capabilities. Assumptions of inherent safety based solely on nanoscale size or biodegradability are similarly premature in the absence of comprehensive long-term toxicity and immunogenicity data. Furthermore, excessive complexity in multifunctional nanocarrier design may impede clinical translation if manufacturing reproducibility, cost, or regulatory approval becomes prohibitive. A balanced, evidence-driven approach that distinguishes achievable near-term advances from longer-term aspirations will be essential to ensure credible, sustainable progress in ocular nanomedicine and its eventual impact on patient care.

Conclusion

Nanocarrier systems represent a clinically meaningful advance in ocular pharmacotherapy, addressing the fundamental pharmacokinetic constraints imposed by the precorneal, corneal, and posterior segment barriers that restrict conventional formulations to below 5% bioavailability. Across the range of conditions reviewed, from anterior segment inflammation and infectious keratitis to sight-threatening posterior segment disorders including diabetic retinopathy, age-related macular degeneration, and retinoblastoma, multiple nanocarrier platforms have demonstrated consistent preclinical benefits in drug permeation, controlled release, and target tissue accumulation. Liposomes and polymeric nanoparticles have achieved the greatest translational traction, evidenced by approved clinical formulations, and provide a proven benchmark for emerging platforms. Realising the full potential of ocular nanotechnology will require standardised manufacturing, comprehensive long-term safety evaluation, and rigorously designed clinical trials anchored to patient-relevant endpoints. Nanotechnology is most credibly positioned as a targeted enhancement to existing ocular delivery strategies; its greatest near-term impact lies in conditions where sustained local drug exposure materially reduces treatment burden and improves patient adherence.

Key takeaways: (i) lipid-based and polymeric nanocarriers currently offer the strongest translational evidence and should be the preferred platforms for near-term clinical development; (ii) posterior-segment delivery via non-invasive topical administration remains a preclinical aspiration requiring substantially more validation before clinical claims are appropriate; (iii) long-term ocular safety, manufacturing scalability, and regulatory compliance must be prospectively integrated into nanocarrier development programmes from early stages; (iv) future clinical trials should prioritise patient-relevant endpoints, such as reduced treatment frequency, improved adherence, or meaningful quality-of-life gains, over surrogate pharmacodynamic measures to establish the case for clinical adoption.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. The section-wise contribution of the authors to the article is as follows:

UPSP (Uday Pratap Singh Parmar): Conceptualisation, search strategy development, literature review, and primary drafting of introduction (Section 1), infectious keratitis (4.3), ocular inflammation (4.5), Figure 1, and future directions (Section 5).

SB (Shilpy Bhullar): Conceptualisation and drafting of nanoparticle types and systems (Section 3).

RBS (Rohan Bir Singh): Drafting of dry eye disease (4.1) and conjunctivitis (4.2) sections.

MS (Maryam Shayan): Drafting of the age-related macular degeneration (4.7) section and Table 1.

RG (Rudraksh Gupta): Drafting of diabetic retinopathy Section (4.6) and Table 1.

AG (Ankit Gauba): Drafting of retinoblastoma (4.8) section and revising Table 2.

KR (Karima Rai): Drafting of retinopathy of prematurity (4.9) section.

PI (Parul Ichhpujani): Drafting of glaucoma section (4.4); overall supervision, revising Tables 1 and 2, and final manuscript structuring.

Disclosure

The authors report no conflicts of interest in this work.