Thymoquinone (2-isopropyl-5-methyl-1,4-benzoquinone) is the major biologically active ingredient of the volatile oil that is isolated from the medicinal plant Nigella sativa (Darakhshan et al., 2015). It has been demonstrated that this herbal ingredient shows neuroprotective, anti-inflammatory, and antioxidant effects (Alhebshi et al., 2013) and is effective in the treatment of glaucoma (Fahmy et al., 2018). Fahmy et al. (2018) reported various liposomal formulations of thymoquinone (TQ) and latanoprost (LAT) in reducing Intraocular pressure (IOP). Addition, this study indicated the promising role of TQ in the amelioration of retinal damage and the inflammatory responses in glaucomatous rabbits (Fahmy et al., 2018).

Catechin (flavan-3-ol) is a member of the flavonoids, a class of natural polyphenols considered an antioxidant ingredient and found in various fruits, beverages, and tea. It has some biological advantages (Shimamura et al., 2007; Singh et al., 2011; Li et al., 2019). The therapeutic applications of catechin for ocular disease has been reported in various studies, including for dry eye, glaucoma, and various retinal disorders due to anti-inflammatory and anti-oxidative properties (Lee et al., 2017a). Lee et al. (2017a) investigated the nano-complex of PEG and catechin for enhancing the bioavailability and the therapeutical effect of catechin in the treatment of dry eye disease (DED). In another study Li and his coworkers employed a simple self-polymerization and self-assembly reaction to formulate a core-shell structure of polycatechin and gold nanoparticles (Au@Poly-CH NPs) as an eye drop to synergistically eliminate DED due to its antioxidant and anti-inflammatory effects (Li et al., 2019).

Epigallocatechin gallate (EGCG) as a major ingredient of green tea, exhibits anti-inflammatory effects and is extensively used in the treatment of various inflammatory diseases and for the treatment of ocular disorders, such as AMD, DR, and DES (Fangueiro et al., 2016). However, the corneal epithelium is an effective barrier for hydrophilic EGCG. Luo and Lai (2017) designed new biodegradable gelatin-g poly (N-isopropyl acrylamide) (GN) nanocarriers for the topical administration of EGCG on rabbit eyes in the treatment of DED with anti-oxidant activity and sustained release profile (Luo and Lai, 2017).

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] is the yellow-colored bioactive component of turmeric powder, extracted from the rhizome of the plant Curcuma longa (Aggarwal et al., 2003) with a wide verity of physiological and pharmacological characteristics (Sharma et al., 2005; Shishodia et al., 2005; Sadeghi Ghadi and Ebrahimnejad, 2019; Sadeghi-Ghadi et al., 2020). Curcumin (CUR) is also considered as an effective ingredient for the treatment and prevention of various ocular disorders such as glaucoma, cataract, corneal and choroidal neovascularization, AMD, DR, DES (Radomska-Leśniewska et al., 2019). It can be beneficial in the treatment of proliferative epithelial disorders, the proliferation of human lens epithelial cells, and protects retinal cells, retinal ganglion cells, and corneal epithelial cells (Beevers and Huang, 2011). One of the major challenges with curcumin is low stability and storage difficulties. In order to overcome these problems, Maharjan et al. (2019) investigated different approaches to formulating curcumin or tetrahydrocurcumin (THC)-loaded in various derivatives of hydroxypropyl (HP)-cyclodextrins (CD) by applying the spray drying technique. It was reported that the stability, bioavailability and corneal and retinal epithelial permeability of curcumin (or THC) was significantly enhanced by encapsulating into the HP-CDs (Maharjan et al., 2019).

Berberine (BBR), a type of isoquinoline alkaloid, is an active ingredient of Rhizome Coptidis and Cortex Phellodendri and extensively used in China for treating a variety of disorders (Lin et al., 2015; Choi, 2016; Wen et al., 2016). In order to improve the therapeutic effects, thermal stability of berberine and prevent it from oxidation, Lai and his coworkers investigated new liposomal formulations coated with G3 polyamidoamine dendrimer (PAMAM G3.0) for the treatment of AMD disease. They used berberine hydrochloride (BBH) and chrysophanol (CHR) in their formulations due to their anti-inflammatory and anti-angiogenesis effects for ocular drug delivery applications, respectively (Lai et al., 2019). According to previous studies, CHR can be beneficial in the treatment of retinal disorders due to its ability to suppress NF-κB/caspase-1 activation that leads to reduced inflammatory responses (Kim et al., 2010).

Pilocarpine, an alkaloid with an imidazole ring, is extracted from the leaves of the Jaborandi plant. It can be applied as a miotic agent for topical administration in glaucoma treatment. However, the corneal permeation of pilocarpine is restricted due to its high hydrophilicity that results in low ocular bioavailability. Nair et al. (2012) encapsulated pilocarpine in Poly (lactic-co-glycolic acid) (PLGA) nanoparticles to improve miotic effect and enhance the bioavailability and ocular retention time of pilocarpine.

Genistein (4,5,7-trihydroxyisoflavone) is a flavonoid that’s abundant in soy products and has numerous pharmacological properties such as anti-oxidative, anti-inflammatory, and anti- angiogenesic (Aldina et al., 2019). It also considered a beneficial factor in the treatment and prevention of eye diseases, including DED, DR, AMD, cataract formation, and glaucoma (Lin et al., 2016). Genistein (GEN) can protect the cornea through its anti-inflammatory effect by suppression of oxidative stress (Xiao et al., 2018). It can also suppress IL-1β in the dry-eye model rat. Genistein can be used to prevent posterior capsular opacification (PCO) that’s the most common complication that occurs after cataract surgery due to the remained epithelial cells in the capsular bag that’s proliferated or migrated after cataract surgery which causes blurred vision (Spalton, 1999). So, genistein as an inhibitor of the growth of epithelial cells, can effectively reduce the frequency of PCO and enhance patient satisfaction after cataract surgery (Zhang et al., 2013).

Resveratrol (trans-3,5,4′-trihydroxystilbene) is a non-flavonoid polyphenol compound that widely exists in dietary sources including grapes and peanuts. It has various therapeutic effects (Lee et al., 2011; Abengózar-Vela et al., 2019) and it also considered as a potential ingredient to prevent ocular disorders, including glaucoma, AMD, cataract, and DR (Bola et al., 2014) due to its free radical scavenging properties (Anisimova et al., 2011; Natesan et al., 2017). The small size and hydrophilic characteristics of resveratrol (RES) enables it to pass through the cornea and enter into the retina, however, the low bioavailability of RES restricts its applications. Several novel carriers have been explored for RES such as liposomes (Cote et al., 2015), β-cyclodextrin nanosponges (Abdallah et al., 2015), chitosan nanoparticles (Chuah et al., 2013), solid lipid nanoparticles (SLN) (Hippalgaonkar et al., 2013), protein complexes (Sahoo et al., 2011), poly-ε-caprolactone (PCL) (Wu et al., 2005), to overcome the low solubility, bioavailability, and stability issues of RES. Dong et al. (2019) synthesized gold nanoparticles (AuNPs) without utilising any harmful reductants. Resveratrol is used as a stabilizer and reducing agent in the fabrication of AuNPs. This formulation can reduce the permeability of the blood-retinal barrier in streptozotocin (STZ)-induced diabetic rats. According to the study’s findings, the number of retinal vessels and the expression of the vascular endothelial growth factor (VEGF-1) was decreased whilst the expression of renal pigment epithelium-derived factor (PEDF) increased in the retina of diabetic rats after administration of AuNPs (Dong et al., 2019).

Quercetin is the major prevalent flavonoid that is extensively found in various sources such as apples, tea, onions, nuts, berries, cauliflower, cabbage, and many seeds. Quercetin has many beneficial effects in the treatment and prevention of various diseases (Abengózar-Vela et al., 2019). It is beneficial in ocular disorders such as cataract, choroidal neovascularization (CNV), and AMD (Zhuang et al., 2011). It has antiangiogenic activity and a protective effect on human retinal pigment epithelium cells (Adelli et al., 2013). Subramanian et al. loaded RES and quercetin (QUR) in chitosan nanoparticles to reduce IOP in the glaucoma treatment (Natesan et al., 2017).

Naringenin [2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a flavonoid that belongs to the flavanones subgroup, is extensively found in several citrus fruits, figs, bergamot, and tomatoes. It has been shown to be useful in certain disorders (Salehi et al., 2019) including a beneficial effect on ocular disorders such as retinal pigment epithelium degeneration (RPE), choroidal neovascularization (CNV), and AMD and has attracted attention in recent years. Zhang et al. (2016) encapsulated Naringenin (NG) into sulfobutylether- β-cyclodextrin/chitosan nanoparticles (NG-CD/CS-NPs) for topical administration of the drug to treat AMD disorder.

Lutein is a hydrophobic carotenoid with anti-oxidative and anti-inflammatory properties (Chang et al., 2018) and is found in green leafy vegetables, yellow fruits, petals of the marigold flower, orange, broccoli, spinach, kale, cilantro, corn, and egg yolk (Wallace et al., 2015). Lutein is found at high concentrations in macular pigment in the retina and functions as a light filter to protect the macula from UV-light and anti-oxidative damage. It has a protective effects in the treatment and prevention of ocular diseases (especially posterior eye diseases) such as DR, macular degeneration (MD), neuronal injury, AMD, uveitis, choroidal neovascularization, retinal ischemia, retinitis, and cataract (Koushan et al., 2013; Buscemi et al., 2018). Despite all these beneficial effects, the low stability, bioavailability, and solubility of lutein hinders its medicinal applications (Toragall et al., 2020). Liu et al. (2014) developed lipid nanoparticles and cyclodextrin for topical administration of lutein. This formulation was more successful in accumulating and partitioning lutein in the cornea, enhanced drug loading efficiency, stability, and decreased cytotoxicity than nanoparticles without lutein (Liu et al., 2014).

Kaempferol [3,5,7- trihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one] is a natural flavonoid that is found extensively in edible plants and fruits with high anti-oxidative, anti-inflammatory, anticancer, anti-angiogenesis, and antimicrobial activities (Hung et al., 2017; Du et al., 2018). In ocular disorders, it has attracted interest for the topical treatment of corneal neovascularization and its protective effect on RPE cells from reactive oxygen. Chuang et al. (2019) applied Kaempferol (KA) to hinder vessel formation and treat corneal neovascularization. To increase the bioavailability and sustained release of KA, it was loaded into gelatin nanoparticles (GNP) for administration as eye drops for ocular drug delivery (Chuang et al., 2019).

Baicalin (5,6-dihydroxy7-O-glucuronide) is a flavonoid with low water solubility and stability and is extracted from the Scutellaria baicalensis Georgi plant (Ashraf et al., 2018). Baicalein, baicalin, and wogonin are among the major bioflavonoids extracted from it. They can be used for the treatment of various diseases (Natesan et al., 2017; Sowndhararajan et al., 2018). They exhibit a broad spectrum of biological activities in the eyes, such as anti-inflammatory, antibacterial, anti-cataract, antioxidant, and anti-angiogenesis effects and can be effective in the treatment of AMD, DR, and uveitis (Natesan et al., 2017).

Ashraf et al. (2018) formulated three different nanostructural systems to enhance baicalin (BN) pharmacological and physiological properties (Liu et al., 2009). In other studies, the efficiency of SLN and NLC for the delivery of baicalin for the treatment of cataractic rats was investigated (Liu et al., 2011).

Tetrandrine (6,6′,7,12-tetra methoxy-2,2′-dimethyl-1 beta-berbamane) is an alkaloid extracted from the Chinese medicinal herb Radix Stephania tetrandrae S with anti-inflammatory, immunologic and antiallergenic effects. It has beneficial effects on ocular disorders and can be used in the treatment of opacification of the posterior lens capsule, cataracts, glaucoma, chronic keratitis, retinopathy, and ocular inflammations (Huang et al., 2011). Li et al. loaded tetrandrine in cationic solid lipid nanoparticles (TET-CNP) and anionic solid lipid nanoparticles (TET-NP) to enhance the bioavailability of TET (Liu et al., 2016a). They demonstrated that negatively charged NPs are more efficiently uptaken into the cellular human lens compared to the cationic TET-CNP, thus the formulation could be effective in PCO treatment (Li et al., 2014).

Polymeric nanoparticles (PNPs) are carriers composed of biodegradable and biocompatible natural or synthetic polymers, with or without mucoadhesive properties. Both synthetic polymers such as polyacrylamide, polyacrylate, PCL, PEG, and PLGA (Ebrahimnejad et al., 2009; Wilczewska et al., 2012) and natural polymers such as gelatin, albumin, DNA, sodium alginate, carboxymethylcellulose sodium (CMC), and chitosan can be used to produce PNPs (Varshochian et al., 2015; Madni et al., 2017). They can deliver drugs from either active ingredients adsorbed on the surface or by having it encapsulated into the particle itself. Nanoparticles can be classified as nanospheres (NSs) and nanocapsules (NCs). NSs represent a matrix delivery system where a drug is adsorbed on the surface of the matrix or dispersed within it (Khalili and Ebrahimnezhad, 2017; Omerović and Vranić, 2019). NCs are vesicular systems where the inner core has different properties to the outer polymeric layer and they consist of film polymeric cover wrapping around an oil-filled chamber with a size distribution typically in the range from 10 to 1,000 nm (Paolicelli et al., 2010). In these systems, a drug is commonly dispersed in the core of the particle, but it may also be adsorbed on the surface. The drug loading efficiency is dependent on the affinity between drug and polymers, and the number of functional groups in the polymers for interaction with drugs. In one study, Lee and his coworkers synthesized two types of nanoparticles for long-term and prolonged release of pilocarpine in glaucoma therapy. They used poly (ε-caprolactone) to prepare nanocapsules and nanospheres harboring or encapsulating drugs for ocular drug delivery. It was demonstrated that the loading efficiency of pilocarpine in the PCL NCs was significantly higher than that the PCL NSs and drug release followed a sustained release pattern. The bioavailability, degradation rate, and in vivo experiments on rabbit eyes indicated that PCL NCs are a promising carrier for the treatment of glaucoma, and most effectively reduced the intraocular pressure of rabbit eyes (Lee et al., 2017b). Ruginǎ et al. (2019) loaded RES as an anti-VEGF agent in micro/nanocapsules [composed of polyelectrolytes coated with rhodamine 6G (Rh6G)] to deliver RES into retina pigmented epithelial D407 cells to treat diabetic retinopathy. In another study, Kim et al. (2019) formulated nanospheres with bovine serum albumin and evaluated the potency of antioxidant protection of rosmarinic, ursolic acid, and curcumin in the retina epithelial cells. It was demonstrated that these formulations increased drug solubility and bioavailability and decreased the production of ROS in retina tissues, thus albumin nanospheres could be a promising carrier to deliver anti-oxidative drugs to the anterior and posterior chamber of the eye. There are a number of approaches that can be considered to enhance the absorption of nanoparticles by increasing the retention time such as the use of mucoadhesive polymers, and optimizing nanoparticle size (Ebrahimnejad,, 2009; Ebrahimnejad et al., 2011; Tahara et al., 2017; Sharifi et al., 2019). Bodoki et al. (2019) developed novel nano-formulation by using zein and PLGA nanoparticles to form nano-gels with mucoadhesive and thermosensitive properties for topical administration to enhance the bioavailability, stability, and retention time of lutein for ocular drug delivery. The efficiency of these formulations was evaluated on the selenite-induced rat model of cataracts. The obtained results demonstrated that topically applied lutein-NPs significantly reduced the cataract intensity in comparison to free ocular lutein and oral delivery (Bodoki et al., 2019). Recently, polymeric nanoparticles in the size range from 10–200 nm have gained considerable attention as carriers for ocular drug delivery (Sabzevari et al., 2013; Badiee et al., 2018), due to their ability to enhance bioavailability (Ogunjimi et al., 2017). This indicates that increasing the size of functionalized nanoparticles decreases bioavailability. Therefore, to target the posterior segment of the eye the functionalized nanoparticles size should be kept around 200 nm. The physicochemical properties of nanoparticles enhanced absorption and penetration to the retinal glial cells. Nanoparticle charge is an important parameter, for example changing the negative charge particle to become cationic resulted in NPs penetrating deeper into ocular tissues (Madni et al., 2017; Bisht et al., 2018).

PEGylation is one of the most frequently used approaches to modify the surface of carriers in order to influence the permeability, retention time, and absorption of drugs. Pandian et al. (2016) applied PEG to surface modify chitosan nanoparticles. Resveratrol (RES) was used as a drug model for glaucoma treatment and loaded into nanoparticles. The results indicated an excellent correlation between an increase in PEG concentration and the size and polydispersity index of formulated nanoparticles. The release profile of RES indicated an initial burst release that was followed by a sustained release profile. The irritation test of formulations was evaluated by Hen’s Egg test and results demonstrated the safety of these formulations for ocular drug delivery. These surface modified formulations significantly reduced the IOP within rabbit eyes and enhanced drug permeation through the cornea (Pandian et al., 2016). Chang et al. (2017) developed gelatin/epigalloccatechin-3-gallate nanoparticles coated with conjugated complex comprised of an arginine–glycine–aspartic acid (RGD) peptide grafted to hyaluronic acid (HA) to target α_vβ₃ integrin on human umbilical vein endothelial cells (HUVECs) for treatment of corneal neovascularization of mouse eye. Surface plasmon resonance was used to confirm to the binding of NPs to the integrin α_vβ₃. The drug release demonstrated a sustained release profile. These nanoparticles are considered a promising carrier to inhibit the vascular endothelial cells and target the specific site of action (Chang et al., 2017).

Micelles are composed of monolayers of amphiphilic agents (e.g., lipids, polymers) that can self-assemble in aqueous media. The particle size of micelles range between 10 and 100 nm. Micelles show more ordered structures than liposomes but exhibit various structures that depend on the hydrophobic and hydrophilic properties of molecules and solvents. The concentration of polymers in solution is a determining factor in the formation of micelles thus the critical micelles concentration should be attained in order to obtain core-shell nanocarriers with a hydrophobic core and a hydrophilic shell (Cagel et al., 2017). Hydrophobic drugs and active ingredients can be encapsulated and protected in the hydrophobic core of micelles in order to deliver them to the target site and enhance permeation of drugs through the epithelial layers which leads to reduced side effects and increased bioavailability. The hydrophobic shell can be utilized to control release and also specific targeting by immobilizing targeting moieties on the surface of micelle. Li et al. (2017) formulated curcumin nanomicelles as a topical ophthalmic formulation decorated with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCL-PVA-PEG) as a graft copolymer. This functionalized nanomicelles improved the solubility, stability, encapsulation efficiency, antioxidant properties of curcumin, and was well tolerated in rabbit eyes. Moreover, it enhanced the corneal permeation and anti-inflammatory properties of curcumin, indicating it as a promising carrier in ophthalmology (Li et al., 2017). Additionally, nanomicelles demonstrate a low critical micelles concentration, stability in solution, a high solubilization capacity, and low cytotoxicity (Mandal et al., 2017). The mucoadhesive nature and small size of polymeric micelles were evaluated and the results from both in vitro and in vivo animal studies indicate that polymeric micelles can enhance contact time with the ocular surface and improve drug transport through intraocular tissues via the paracellular route (Suri et al., 2020). Moreover, the hydrophilic nature of polymeric micelles produces clear solutions that can be used in the form of eye drops without any visual disturbance. Polymeric micelles can therefore be considered as one of the most promising techniques in ocular drug delivery for the treatment of both anterior and posterior segment of eye diseases such as DES, AMD, DR, glaucoma (Alviset et al., 2022), endophthalmitis, retinitis and corneal or conjunctival squamous cell carcinoma (Madni et al., 2017). Li et al. (2020a) evaluated a Soluplus micelle of resveratrol (SOL-RES) for corneal wound healing. In a separate study of cellular uptake and corneal permeation, coumarin-6 loaded within nanomicelles. The irritation test and histopathological observation of rabbit corneas were evaluated 24 h after eye drops instillation and results indicated good ocular tolerance and no eye irritation (Li et al., 2020a).

Nanofibers are fibers with diameters in the range of 1–100 nm. They provide a large surface area up to 1,000 m² per Gram that can enhance drug loading capacity (Deepak et al., 2018). Various natural (e.g., chitosan, fibronectin, gelatin, collagen, silk, and ethylcellulose) or synthetic polymers (e.g., PLA, PGA, PLGA, PEO, PCL, and PVA), or combinations can be used to produce nanofibers through the electrospinning process. Nanofibers can be modified by varying parameters such as the concentration of polymer solution and drug, adjusting porosity (Goyal et al., 2016), morphology and the diameter of fibers. Moreover, they can be functionalized to modulate the drug release (Zong et al., 2022). They can provide sustained-release profile that results in a reduction in the frequency of administration and thus enhance patient compliance (Gelb et al., 2022). Attractive physical properties of nanofibers such as the high surface-area-to-volume ratio, high porosity, flexibility, high drug-loading capacity, biocompatibility, biodegradability and increasing the contact time of drug with target tissues make them a unique candidate for drug delivery applications, diagnosis and treatment of different diseases, particularly for chronic ocular diseases that require frequent drug administration. Moreover, they can provide a surface for growth, attachment, differentiation, and proliferation of cells (Goyal et al., 2016). Forouzideh et al. (2020) investigated the beneficial anti-angiogenesis effect of silk fibroin nanofibers (SFNF) loaded EGCG on corneal tissue. The nanofibers prepared by electrospinning technique were characterized, the drug release studies of nanofibers showed a controlled release pattern over 144 h, and drug loading of EGCG into the silk fibroin nanofiber reported at approximately 8.0%. MTT assay and human umbilical vein endothelial cells (HUVEC) were used to determine the toxicity and appropriate dose of the drug. Results demonstrated EGCG in nanofiber lead to inhibition of HUVEC and provide an appropriate environment for hosting and proliferation of limbal cells. Moreover, SFNFs with a rough surface provide good conditions for attachment and adhesion of cells on the surface of nanofiber that makes it a promising scaffold for corneal tissue engineering (Forouzideh et al., 2020).

Dendrimers are nano-sized, three-dimensional, hyperbranched, and typically star-shaped structures with many arms emerged symmetrically from a central core (Patri et al., 2002). The size of these structures is related to the various generations (G0, G1, and G2, etc.). Dendrimer nanoparticles can be produced by fast reduction and nucleation reactions (Crooks et al., 2001). The size of dendrimers is usually smaller than 100 nm. The synthetic dendrimers most commonly used in nanomedicine include polyamidoamines (PAMAM), poly (l-lysine) (PLL), polyesters (PGLSA-OH), polypropylimines (PPI), poly (2,2-bis (hydroxymethyl)propionic acid), and aminobis (methylenephosphonic acid) (Mignani et al., 2013). Hydrophobic drugs can be encapsulated in the core or entrapped among the branches of dendrimers based on the properties of polymers used in their construction. The surface of dendrimers can be modified by attaching molecules that may result in increasing the interaction of the dendrimer with biological membranes and high drug payloads. The small size, multi-functional properties, high drug loading ability, water-solubility, targeting ability by surface modification, bioavailability, and biocompatibility make dendrimers a promising candidate for drug delivery (Yavuz et al., 2015; Rodríguez Villanueva et al., 2016). Moreover, their low polydispersity index prevents them from uptake by the reticuloendothelial systems, thus enhancing drug permeation. PAMAM dendrimer have been the main family of dendrimers investigated for drug delivery (Chaplot and Rupenthal, 2014). Yang et al. (2012) indicated that the bioavailability of anti-glaucoma drugs in the cornea of rabbits was enhanced and intraocular pressure decreased by using a hybrid of PAMAM dendrimer hydrogel/PLGA formulation (Yang et al., 2012). PAMAM dendrimer could be used to reduce the frequency of topical ocular administration. The influence of size, molecular weight and various type of surface groups in poly PAMAM dendrimers was investigated in a controlled ocular drug delivery by Vandamme et al. Pilocarpine and tropicamide were loaded in different dendrimer formulations to evaluate the miotic and mydriatic activities, the tolerability, and residence time of dendrimer solutions on the ocular surface of rabbits. The obtained results indicated that the retention time of dendrimers with carboxylic and hydroxyl surface groups was longer than the other formulations. However, altering dendrimer concentration had no significant effect. Moreover, this study demonstrated the influence of size, molecular weight, charge, and geometry of dendrimers on ocular residence time (Vandamme and Brobeck, 2005).

Lipid nanoparticles (LNPs) can be considered as oil/water (o/w) emulsions where liquid lipids are replaced with solid lipids at room temperature. LNPs can provide prolonged drug release with negligible toxicity, so they may be explored as promising carriers for ocular therapeutics. LNPs are classified into two groups: solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) (Omerović and Vranić, 2019). SLNs are colloidal lipid-based systems with an average diameter from 50 to 1,000 nm (Müller et al., 2000) and composed of high melting point lipids, water, surfactants, and cosurfactants that stabilize the liquid dispersion (Lingayat et al., 2017). A broad spectrum of lipids can be used to produce SLN include triglycerides, partial glycerides, fatty acids, steroids and waxes (Mehnert and Mäder, 2012; Dudhipala, 2019). Different methods can be applied to produce SLNs such as hot homogenization methods, micro-emulsion method, coacervation method, solvent evaporation, and solvent diffusion from emulsions, solvent injection method, ultrasonication, supercritical fluid extraction of emulsions, and precipitation method (Mukherjee et al., 2009; Silva et al., 2011; Battaglia et al., 2014; Naseri et al., 2015; Rajpoot, 2019). SLNs can be used for different routes of drug administration such as oral, rectal, topical, ophthalmic, parenteral, and other routes (Azhar Shekoufeh Bahari and Hamishehkar, 2016; Beloqui et al., 2016; Bhagurkar et al., 2017). SLNs have the ability to entrap hydrophilic and hydrophobic drugs, are physically stable, prevent the degradation of encapsulated drug, enhance drug bioavailability and biocompatibility (based on the kind of lipids used), and a production process that is simple and cost-effective (and without requiring organic solvents), and the ability to be sterilized and produced at an industrial scale (Beloqui et al., 2016). The biocompatibility and mucoadhesive properties of SLNs, cause to enhance their interaction with the eye mucosa and drug retention time on the eye surface and let it pass the corneal barrier. The negatively charged epithelium provides an opportunity for cationic SLN particles to enhance the drug retention time on the eye and increase its absorption (Bonilla et al., 2022). Despite the numerous advantages, SLNs suffer from numerous disadvantages such as limited drug loading due to the solid crystalline state of the nanoparticles and burst release of both hydrophilic and hydrophobic drugs to the solubility of the drug in the lipid melt (especially remarkable in hydrophilic drugs via adsorption to the surface of SLNs and in polar drugs via existence in outer surfactant layer). Thus, the second generation of lipid nanoparticles introduced to eliminate these drawbacks were NLCs that composed of a mixture of solid and liquid lipids. Different kinds of NLCs can be prepared by applying various concentrations of liquid lipids and different methods of production. Utilizing the liquid lipid in the NLCs leads to enhanced drug loading, increased drug solubility, and reduces the crystallization of solid lipid that minimises the burst release of drug (Tian et al., 2012). NLCs have been extensively applied for anterior and posterior segment ocular drug delivery via corneal and non-corneal pathways (Tian et al., 2013; Zahir‐Jouzdani et al., 2019). The size and surface charge of lipid nanoparticles have an important role in the potential targeting and the extent of drug permeation, in this approach reducing the size of LNPs increases trans-corneal absorption (Kalam et al., 2010) and a positive charge results in higher permeation than a neutral or negative charge and enhances the retention time of nanoparticles on the surface of the cornea (Tamilvanan and Kumar, 2011), however, cationic particles may cause irritation and have toxic effects on ocular tissue due to a greater electrostatic interaction with the anionic layer of ocular tissue thus non-ionic surfactants and lipids preferred (Naseri et al., 2015; Üstündağ Okur et al., 2015). Fangueiro et al. (2016) evaluated in vivo, ex vivo, and in vitro studies on EGCG loaded cationic lipid nanoparticles (LNPs) produced by the double-emulsion technique. The pharmacokinetic profile of the corneal permeation of EGCG loaded into two different formulations of LNPs were evaluated and obtained results of EGCG cetyltrimethylammonium bromide (CTAB) LNs and EGCG-dimethyl dioctadecyl ammonium bromide (DDAB) showed a Boltzmann sigmoidal profile and first-order kinetics respectively. They utilised natural lipid in the formulations that are considered safe, biocompatible, and biodegradable. These cationic lipids indicated high stability without making no irritation or any toxic effects. The positive charge of these LNPs can interact with negative charge of mucosa on the surface of the eye which leads to higher retention time and enhanced permeation through trans-scleral and trans-corneal pathways (Fangueiro et al., 2016; Bodoki et al., 2019). Yu et al. formulated a hybrid pH and thermo-sensitive hydrogel of NLCs for ocular delivery of quercetin. Carboxymethyl chitosan (CMC), and poloxamer 407 were used in hydrogel construction and genipin (GN) used as a crosslinker. Fluorescence imaging, confocal laser scanning microscopy (CLSM), and ex-vivo transcorneal experiments demonstrated that NLCs enhanced corneal permeability and retention time. To evaluate the cellular uptake an ex-vivo transcorneal study was undertaken. Coumarin 6 was used as a hydrophobic fluorescence marker that was administrated into rabbit eyes. Intraocular permeation and distribution of Coumarin 6 were imaged by CLSM after 30 and 120 min of drug instillation. According to the findings, the corneal retention time followed an order of: NLC-Gel > Gel > NLC > eye drops. Cytotoxicity tests and histological examination demonstrated the safety and cytocompatibility of the NLC-Gel formulation (Yu et al., 2018; Yu et al., 2019; Yu et al., 2020).

Liposomes are spherical vesicles with phospholipid bilayers surrounding an aqueous core. The encapsulated drug in these systems can be protected by the lipid bilayer that leads to controlled drug release (Fakhravar et al., 2016). Phosphatidylcholine, cholesterol, and lipid-conjugated hydrophilic polymers are among the common components found in their structures. The size of liposomes ranges from 25–2,500 nm (Akbarzadeh et al., 2013). Liposomes are biodegradable, biocompatible, and nontoxic carriers that can encapsulate both hydrophilic and hydrophobic drug molecules. Despite these superior properties, liposomes suffer from instability due to the presence of unsaturated lipids in their structures that may be hydrolyzed or oxidized and causes the leakage of encapsulated drug. Moreover, aggregation and fusion of liposomes prevent them from ocular tissue absorption. To overcome this limitation, positively charged liposomes were introduced to increase corneal absorption and resistance time. There are numerous methods for producing liposomes which include: thin-film hydration (Zhang, 2017; Zhao et al., 2017), size reduction sonication, reverse-phase evaporation (Shi and Qi, 2018), solvent injection (Sharma et al., 2018), detergent depletion (Salimi, 2018), supercritical fluid process (William et al., 2020), high-pressure homogenization (Ibišević et al., 2019), and low-pressure extrusion (Rameez et al., 2010). Liposomes can be considered as a good carrier for sustained and triggered drug release (Oude Blenke et al., 2013) and have the potential to use for ocular drug delivery (Vafaei et al., 2015; Goyal et al., 2016). They are able to increase the contact time within ocular tissues, thus improve drug absorption and enhance ocular bioavailability and also patient satisfaction due to reducing the dosing frequency. In liposomal systems, drugs can be protected against enzymatic degradation in tear film or/and corneal epithelium which results in a reduction in the clearance rate of the formulations (López-Cano et al., 2021). Mucoadhesive and permeation properties of liposomes can be enhanced by surface modification. Surface charge and size of liposomes have a great effect on ocular drug delivery and the degree of drug permeation into ocular tissues. The critical role of size and charge of liposome on corneal permeation was considered by Schaeffer and Krohn where they applied the formulations in rabbit models. They demonstrated that the permeation of topically administrated formulation through the cornea of rabbits increased in the order small cationic unilamellar vesicles (SUV+) > multilamellar anionic vesicles (MLV-) > small anionic unilamellar vesicles (SUV-) > SUV > MLV free drug (Lakhani et al., 2018a; Venkatraman et al., 2018). In another study, Hironaka et al. (2009) indicated that liposomes smaller than 200 nm show better absorption into retinal tissue whilst particles larger than 600 nm exhibit minimal absorption. According to the obtained results, liposomes can enhance the pharmacokinetic profile of drugs so they can be applied for the treatment of the anterior and posterior segment of the ocular diseases such as glaucoma, DME, ARD, DR, endophthalmitis, retinitis, and corneal or conjunctival squamous cell carcinoma (Kompella et al., 2013). However, the applicability of liposomes has been hindered by issues such as low stability and poor reproducibility, low encapsulation efficiency, uptake by the reticuloendothelial system during phagocytosis, and cause visual cloudiness when intravitreal injected. ER et al. (2021) loaded curcumin and rhodamine B (RhB) dye into multilamellar liposome (MLV) by the thin-film hydration method. They used sodium alginate (SA) and acrylic acid (AA) grafted to each other through a radical polymerization method. Since riboflavin (RB) works as a transporter through the blood retina barrier (BBB), it was conjugated to the produced SA-g-AA to facilitate efficient delivery into the retina region. The resultant product (SA-g-AA-RB) was coated on the surface of the produced MLV using the o/w emulsion method that followed by ionotropic gelation to construct MLV-SA-g-AA-RB carriers that are able to target the retinal region. This formulation produced a prolonged-release profile, good membrane permeability, cellular absorption, and good bioavailability. The size of MLV-SA-g-AA-RB was reported at 730.5 nm while the size of MLV-SA-g-AA with CUR and RhB was 981.7 nm. The results demonstrated that the small size of liposomes produce higher uptake by cells. The encapsulation efficiency (EE) of CUR and RhB was 61 and 66%, respectively, and both showed a controlled manner of drug release. These formulations can be considered as an appropriate carrier to target and deliver drugs to the retina tissue (ER et al., 2021). In another study, Ibrahim et al. (2019) evaluated the protective and anti-oxidative effects of liposomal forms of lutein in cisplatin-induced retinal injury in rabbit eyes. Liposome prepared by the thin-film hydration technique were injected into the peritoneal cavity. Intraperitoneal injections were repeated twice per week for 2 weeks. The rabbit retina was analyzed by the Comet assay, electroretinogram (ERG), and histopathological examination. The result demonstrated that liposomal lutein formulation could be beneficial to avoid the deleterious effects of cisplatin on the rabbits’ retina and prevent DNA and histopathological damage (Ibrahim et al., 2019).

Niosomes are formed by the self-assembly of non-ionic surfactants that form closed bilayer vesicles in aqueous media. They are biocompatible and biodegradable in nature. They are able to entrap both hydrophilic and hydrophobic drugs (Sadeghi Ghadi et al., 2019). They have enhanced chemical stability, mechanical rigidity, safety, bioavailability, and entrapment efficiency compared to liposomes (Gan et al., 2013). However, hydrolyzation and leakage of the drug are the major disadvantages of niosmes. To improve the stability of niosomes against enzymatic degradation, cholesterol can be used in their formulations. Solulan, chitosan, carbopol, and dicetylphosphate are among the non-ionic surfactants that are utilized for ocular formulations (Wadhwa et al., 2009). Niosomes are considered a promising system for topical drug delivery to the eye for the treatment of ocular disorders due to controlled drug release, ability to deliver drug to the target site with no ocular irritation or side effects, and enhanced bioavailability (Sultana et al., 2011). Jain et al. (2020) developed a niosomal gel formulation of pilocarpine instilled into the lower conjunctival sac of rabbit eyes for glaucoma treatment. Pilocarpine niosomes prepared by the ether injection technique, a nonionic surfactant such as Span 20, 60, 80, and various molar ratios of cholesterol evaluated to optimize the niosomal formulation. The optimized formulation integrated into Carbopol 934 and locust bean gum-based gels. Pilocarpine niosomal gel formulation enhances the bioavailability, stability, and precorneal retention time of niosomes. This study showed that this formulation effectively reduced the IOP of glaucomatous rabbits and prolonged the release profile of pilocarpine. Draize’s test demonstrated that these formulations were safe for ocular tissues, with no signs of irritation observed during the study period (Jain et al., 2020).

Aboali et al. (2020) investigated the anti-inflammatory effects of curcumin loaded in niosomal gel on rabbit eyes and found that the formulation reduced inflammation by the same amount produced by marketed corticosteroids (40%) with minimal side effects. Cremophore RH, lecithin, and cholesterol were used as nonionic surfactants in the preparation of pronisomes. These spherical and uniform proniosomes increased the corneal permeation and resistance time. The corneal permeation of proniosomal gel formulation was 3.22-fold higher than curcumin dispersion. The formulation efficiency in lowering ocular pressure and anti-inflammatory effects was evaluated by eye drop instillation every 4 h for 6 days. The measurement of IOP before and after 8 h of instillation indicated that marketed corticosteroids increased the IOP (1.5-fold) more than the curcumin pronisomal gel and curcumin suspension (Aboali et al., 2020).