The appeal of lipid carriers begins with basic biochemistry. The eye’s surfaces are lipid-rich, so nanoparticles built from phospholipids and related molecules interact naturally with the tear film, extending residence time and sustaining drug release in the conjunctival sac. Some lipid ingredients have a high affinity for cell membranes and actively promote absorption, while others function as permeation enhancers in their own right. Liposomes go one step further: their phospholipid bilayers mimic the structure of cell membranes, which facilitates uptake. Crucially, these systems are also well tolerated, rarely irritating the ocular mucosa—a decisive advantage for chronic conditions requiring daily, sometimes lifelong, administration.

Liposomes, spherical vesicles in which an aqueous core is enclosed by one or more phospholipid bilayers, are the most mature of the three technologies. They range from small unilamellar vesicles of 20 to 200 nanometers up to multilamellar structures spanning 1 to 5 micrometers, and they can carry both water-soluble and oil-soluble drugs simultaneously. Their most powerful design trick is surface charge. Positively charged, or cationic, liposomes bind electrostatically to the negatively charged sialic residues of mucin and to sulfated proteoglycans in cell membranes, anchoring the particles to the ocular surface long enough for uptake to occur. This single modification has produced some of the most striking results in the field.

In one recent study, cationic liposomes roughly 300 nanometers in diameter with a surface potential of +30 millivolts were loaded with tacrolimus for dry eye treatment. The formulation prolonged ocular retention and raised corneal drug concentrations substantially, and it outperformed commercial drops on a key clinical metric: tear film break-up time improved by 3.57 seconds versus 1.50 seconds with the marketed product. Inflammation markers fell in parallel—interleukin-1β concentrations dropped to 99.91 picograms per milliliter, compared with 138.98 for commercial drops and 228.99 in the positive control group. Even more strikingly, a separate 2025 investigation showed that cationic liposomes can scavenge cell-free DNA, a molecule elevated in dry eye patients that destabilizes the tear film and drives surface inflammation. After one week of topical treatment in mice with induced dry eye, the liposomal dispersion restored tear secretion, goblet cell counts, and the corneal barrier itself.

The pharmacokinetic gains from liposomal encapsulation can be dramatic. When acyclovir was delivered to rabbits in positively charged phosphatidylcholine-based liposomes, the relative area under the curve in the aqueous humor was 11.9—more than eleven times higher than an equal concentration applied as an ointment, an aqueous solution, or a solution mixed with empty liposomes. Ganciclovir in liposomes showed two- to ten-fold higher distribution in the sclera, cornea, iris, lens, and vitreous humor than a simple solution. Besifloxacin loaded into cationic liposomes achieved lower minimum inhibitory and bactericidal concentrations against Pseudomonas aeruginosa than the commercial product Besivance, while permeating more effectively. Astaxanthin-loaded liposomes with a slight positive charge protected rats against superficial punctate keratopathy better than neutral versions, apparently because electrostatic attraction to the corneal epithelium kept the antioxidant where it was needed rather than letting it diffuse into the stroma.

Perhaps the most consequential frontier is the delivery of protein therapeutics without needles. Bevacizumab, an antibody used for retinal vascular disease, currently requires intraocular injection. Researchers found that associating annexin A5 with bevacizumab-loaded liposomes triggered endocytosis and transcytosis through the corneal epithelium, delivering 127 nanograms per gram of drug to the posterior segment and 18 nanograms per gram to the retina after topical administration in rabbits. Coating strategies amplify these effects further: methacrylated hyaluronic acid on liposomal surfaces promoted adhesion to bovine conjunctival tissue and CD44-mediated uptake in human corneal epithelial cells, while maleimide-terminated PEG formed covalent carbon–sulfur bonds with thiol groups in the glycocalyx to anchor particles in place. Combination products are advancing too—timolol and latanoprost co-loaded in oligoethylenimine-functionalized liposomes reduced intraocular pressure in rats for up to five days from a single drop, and liposomal triamcinolone acetonide reached the vitreous and retina of rabbits and four patients with diabetic macular edema without raising intraocular pressure.

Cubosomes, the second major platform, are liquid-crystalline nanoparticles built from amphiphilic lipids such as glyceryl monooleate and phytantriol, stabilized by poloxamers. Their bicontinuous cubic lipid structure resembles the membranes of the corneal epithelium, easing transport into corneal cells, and their components are themselves permeation enhancers. The numbers are compelling: ketorolac in cubosomes achieved 2.07-fold higher transcorneal permeation and 2.24-fold greater corneal retention than a reference solution, while bromfenac sodium in hyaluronan-enriched cubosomes reached an aqueous humor area under the curve of 18.88 microgram-hours per milliliter versus 7.93 for marketed drops. In the infection arena, gatifloxacin-loaded cubosomes cut the minimum inhibitory concentration against drug-resistant Staphylococcus aureus four-fold, from 16 to 4 micrograms per milliliter, and reduced corneal opacity more effectively than the pure drug in infected rats—likely because the cubosomes fused with or adhered to bacterial membranes, improving drug delivery into the pathogens themselves.

Cubosomes are also proving their worth against glaucoma and reaching deeper ocular tissues. Timolol-loaded glyceryl monooleate cubosomes of 142 nanometers lowered intraocular pressure in rabbits from 27.8–39.7 to 21.4–32.6 millimeters of mercury after one week. A dual-loaded formulation carrying dorzolamide hydrochloride and timolol maleate together reduced pressure from 27.28 to 19.40 within four hours, with higher drug exposure than marketed drops for both agents. Acetazolamide cubosomes achieved a 38.22 percent pressure reduction versus 31.14 percent for commercial Azopt drops and 21.99 percent for oral tablets—without systemic absorption, since the untreated eye showed no pressure change. Most remarkably, cationic cubosomes carrying lutein delivered the antioxidant to retinal cells, protected the retina against oxidative stress, enhanced Nrf2 and HO-1 antioxidant gene expression, and were still detectable in the mouse retina seven days after topical instillation as simple eye drops.

Solid lipid nanoparticles, the third platform, consist of a lipid matrix—long- or medium-chain triglycerides, waxes, or fatty acids solid at physiological temperatures—wrapped in a surfactant shell that prevents aggregation. Their small size and lipid composition allow them to pass through the cornea and vitreous toward the retinal layers, and they suit dry eye therapy by protecting polar tear components from evaporation. The evidence spans antifungals to anti-inflammatories: natamycin in solid lipid nanoparticles showed 2.5-fold lower minimum inhibitory concentrations against Aspergillus fumigatus and Candida albicans; ofloxacin nanoparticles coated with chitosan and polyethylene glycol reached two- to three-fold higher ocular concentrations in rabbits; PEGylated latanoprost nanoparticles loaded into contact lenses sustained release for 96 hours; and econazole drops kept corneal drug concentrations above the minimum inhibitory concentration for three hours after a single administration. Even fragile molecules benefit—lutein, an unstable carotenoid, gained resistance to oxygen, light, and heat along with an increased permeability coefficient after encapsulation.

Challenges remain before these systems fully replace conventional formulations. Liposomes suffer from chemical instability through lipid oxidation and ester hydrolysis, and from physical instability through aggregation and fusion, which can dump the entire drug payload prematurely. Sterilization is awkward—autoclaving destroys the vesicular structure, while sterile filtration fails for particles above 200 nanometers. Cubosomes risk phase changes in tear fluid that compromise release profiles, and their high-energy production methods can damage sensitive actives. Solid lipid nanoparticles undergo polymorphic transitions during storage that trigger drug leakage, and their ordered crystal lattices leave little room for payload—problems that nanostructured lipid carriers blending solid and liquid lipids may solve. Yet the trajectory is clear: only liposomes have so far reached FDA-approved products, including Artelac Rebalance liposomal drops with vitamin B12 and Lacrisek liposomal spray with vitamins A and E for dry eye. As the review’s authors conclude, these dispersions can be formulated as modified eye drops that outperform both rapidly eliminated conventional solutions and blurry oily semisolids—pointing toward a near future where nanotechnology quietly turns the humble eye drop into one of medicine’s most precise delivery tools.

Subject of Research: Lipid-based nanosized drug delivery systems for topical ophthalmic drug administration

Article Title: Lipid-based nanosized drug delivery systems in ophthalmology

Article References: Lipid-based nanosized drug delivery systems in ophthalmology. (n.d.). https://doi.org/10.3897/pharmacia.73.e206262

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e206262

Keywords: liposomes, cubosomes, solid lipid nanoparticles, ocular drug delivery, dry eye, glaucoma, nanoparticles, corneal permeation, drug bioavailability, ophthalmology, nanomedicine, tear film