Recent advances and strategies for nanocarrier-mediated topical therapy and theranostic for posterior eye disease

Advanced Drug Delivery Reviews 210 (2024) 115321 Available online 26 April 2024 0169-409X/© 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Recent advances and strategies for nanocarrier-mediated topical therapy and theranostic for posterior eye disease Maria Jo˜ ao Faria a , Jos´ e M. Gonz´ alez-M´ eijome a , b , M. Elisabete C.D. Real Oliveira a , Gonzalo Carracedo c , Marlene Lúcio a , d , * a Centre of Physics of Minho and Porto Universities (CF-UM-UP), Universidade do Minho, Campus de Gualtar, Braga 4710-057, Portugal b CEORLab - Clinical and Experimental Optometry Research Lab, Centre of Physics, Universidade do Minho, Campus de Gualtar, Braga 4710-057, Portugal c Department of Optometry and Vision, Faculty of Optics and Optometry, University Complutense of Madrid, C/Arcos de Jalon 118, Madrid 28037, Spain d CBMA - Centre of Molecular and Environmental Biology, Department of Biology, Universidade do Minho, Campus de Gualtar, Braga 4710-057, Portugal GRAPHICAL ABSTRACT Nanocarrier-mediated topical therapies and theranostic are valuable strategies for targeting posterior ocular tissues. This review exalts safe-by-design approaches in the development of tuneable nanocarriers able to surpass the main ocular barriers. ARTICLE INFO Keywords: Posterior segment of the eye Nanomedicine Nanocarrier-mediated therapies Topical delivery Design strategies Ophthalmic vehicles Theranostic ABSTRACT Posterior eye disorders, such as age-related macular degeneration, diabetic retinopathy, and glaucoma, have a significant impact on human quality of life and are the primary cause of age-related retinal diseases among adults. There is a pressing need for innovative topical approaches to treat posterior eye disorders, as current methods often rely on invasive procedures with inherent risks. Limited success was attained in the realm of topical ophthalmic delivery through non-invasive means. Additionally, there exists a dearth of literature that delves into the potential of this approach for drug delivery and theranostic purposes, or that offers comprehensive design strategies for nanocarrier developers to surmount the significant physiological ocular barriers. This review offers a thorough and up-to-date state-of-the-art overview of 40 studies on therapeutic loaded nanocarriers and theranostic devices that, to the best of our knowledge, represent all successful works that reached posterior eye segments through a topical non-invasive administration. Most importantly, based on the * Corresponding author at: Centre of Physics of Minho and Porto Universities (CF-UM-UP), Universidade do Minho, Campus de Gualtar, Braga 4710-057, Portugal. E-mail addresses: [email protected] (M.J. Faria), [email protected] (J.M. Gonz´ alez-M´ eijome), [email protected] (M.E.C.D. Real Oliveira), [email protected] (G. Carracedo), [email protected] (M. Lúcio). Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/adr https://doi.org/10.1016/j.addr.2024.115321 Received 16 February 2024; Received in revised form 8 April 2024; Accepted 19 April 2024 Advanced Drug Delivery Reviews 210 (2024) 115321 2 successful literature studies, this review provides a comprehensive summary of the potential design strategies that can be implemented during nanocarrier development to overcome each ocular barrier. 1. Introduction The world is facing severe demographic changes, and the prevalence of age-related retinal diseases (ARRD) is increasing globally, mirroring the aging of the world population. By 2020, the Vision Loss Expert Group (VLEG), together with the Global Burden of Disease (GBD) study, estimated that 206 million people were suffering from moderate to severe visual impairment and that the cases of blindness surpassed 33 million [1], with an increase of about 7 million per year [2–4]. Furthermore, most visual disorders occur in the population aged 50 years and older (80%), and the female gender registers higher incidence rates given their longer life expectancy[5]. Age-related macular degeneration, diabetic retinopathy, and glaucoma are the frontline ARRD responsible for visual impairment among adults, affecting mainly the posterior segment of the eye [2]. Treating ocular conditions within this region poses challenges, and it is often dependent on invasive approaches that come with significant limitations, such as potential complications and risk of infection, retinal detachment, vitreous hemorrhage, and cataracts [6]. Besides the adverse consequences on human quality of life, ocular disorders also have profound socioeconomic effects, with an estimated global annual cost of US$3,000 billion ( € 520 billion in Europe) [2]. Altogether, age and gender-related visual loss are societal challenges demanding immediate action when it comes to prevention, early detection, and, most importantly, innovative treatment approaches. The human eye (Fig. 1) is a globe-shaped structure with unique anatomy and physiology [7]. In general, an adult eye is around 24 mm in diameter and may be categorized into two primary regions: anterior and posterior [3,7,8]. The anterior region represents the eye’s frontal part and entails the lachrymal system, lens, anterior and posterior chambers, ciliary body, cornea, conjunctiva, iris, and eyelids [8–10]. Meanwhile, the eye’s posterior portion covers the area from the lens zonula and ciliary muscle to the optic nerve, including specific structures such as the retinal pigmented epithelium, neural retina, sclera, choroid, and the vitreous humor [9,10]. Despite the ocular accessibility for therapeutic administration, the emergence of several physiological and anatomical barriers (e.g., tear turnover mechanisms, physical–chemical barriers of ocular cell membranes, and blood ocular barriers) has always been a challenge to ocular therapeutic delivery [11,12]. For example, systemic delivery is the less effective ophthalmic route of administration given the existence of specialized blood-ocular barriers. These display selective permeability that restricts the penetration of molecules to intraocular tissues (1% a 2%), causing a poor therapeutic outcome in posterior eye disorders [8,9]. As a result, alternative routes, such as intravitreal or periocular (subconjunctival, suprachoroidal, or transscleral) injections, are often selected to reach posterior regions [13]. Even though intraocular injections are effective and allow high drug doses in the posterior segment of the eye, they are intrusive procedures that can result in severe complications [6]. Also, the growing life expectancy and aging of the population do not align with complex and invasive administrations requiring technical expertise. In these circumstances, topical application stands out for its great convenience, as a well-accepted delivery route for the medical management of ocular disorders, particularly those that impact the front area of the eye, such as dry eye syndrome, elevated intraocular pressure (IOP), conjunctivitis, keratitis, and corneal dystrophies [6,14]. To access the tissues located in the posterior portion of the eye, topically applied therapeutics must face three main obstacles: the precorneal region, the corneal barrier, and noncorneal absorption [9]. Considering the limitations imposed by the previously mentioned barriers, only a very short percentage (≤5 %) of topically administered therapeutic agents have conditions to effectively reach the aqueous humor [7,15]. As such, current ophthalmic topical formulations are tailored to deliver small drug molecules and developed for maladies affecting the anterior portion of the eye [12,13,16]. To get beyond these limitations, innovative drug delivery systems have emerged using nanomedicine approaches. Nanomedicine brought new opportunities and promising tools for disease prevention, diagnosis, monitoring, and treatment [17]. The Fig. 1. Diagram depicting the anatomical structures of the eye. The blue and red ocular compartments correspond to the anterior and posterior areas, respectively. M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 3 research conducted in this subject focuses on four main topics: diagnostic imaging (nanodiagnosis), drug delivery (nanotherapy), regenerative medicine, and diagnosis coupled to treatment (theranostics) [18]. The global nanomedicine market is anticipated to keep expanding, reaching $350.8 billion by 2025; drug delivery stands as one of the major driving forces for this trend [19]. To go beyond the inherent hurdles of conventional therapies, nanotechnology-based strategies using nanocarriers hold great promise in therapeutic agents’ delivery. In the particular case of vision sciences, ophthalmic nanocarriers offer the capability to: (i) enhance therapeutic targeting through surface functionalization; (ii) enhance the duration and efficacy of therapeutic effects; (iii) modulate release profiles and maintain therapeutic levels at the target sites; (iv) protect therapeutic payloads and preserve their activity until they reach their target; (v) reduce administration frequency as well as the therapeutic dosage delivered, further mitigating adverse side effects resultant from therapeutic activity or off-target interactions; and (vi) penetrate deeper and overcome the different anatomic barriers of the eye [20]This review focuses on topical nanotechnology-based approaches for therapeutic delivery to the posterior segment of the eye. Up to date, several review articles have addressed therapeutic delivery to the posterior portion of the eye using nanomedicine approaches [14,21–28]. Few, however, have discussed the topical route of administration [10,29,30]. The differentiating factor of the present review is that, unlike the existing literature that offers a broader discussion on delivery methods to the posterior portion of the eye, ours provides a comprehensive list of detailed design strategies that can be implemented during nanomedicine development (i.e., composition, size, charge, deformability, surface modification with targeting moieties or functional coatings, permeation enhancers). The proposed strategies consider the anatomical, morphological, and physicochemical properties of the ocular barriers. Furthermore, another important goal of this review is to provide researchers in the field with a set of tools that will help them make an informed decision when selecting a therapy delivery system. These tools will enable the chosen system to feature the most convenient design and properties to overcome the major ocular barriers to the desired site. Additionally, the inclusion of therapeuticloaded nanocarriers in topical vehicles as a tool to prolong their residence time at the eye’s surface and enhance posterior ocular delivery will also be addressed. The review will also cover innovative topical theranostic devices designed for ocular disorders, with a particular focus on emerging strategies targeting the posterior eye’s region, while referring interesting results obtained in the anterior region. In summary, this review fills a literature gap by focusing on topical administration for delivering therapeutics to the posterior eye. It addresses recent theranostic approaches and specific design strategies for nanocarrier developers to overcome key biological barriers unique to the eye’s structure and function. Moreover, it emphasizes the significance of adhering to applicable guidelines and regulatory standards to ensure a rational design process. The goal of this review is not to detail the different types of nanocarriers or describe their synthesis methods as reported elsewhere [31,32]. Instead, it intends to highlight the role of different types of organic and inorganic nanocarriers in delivering therapeutic agents to the eye. As so, this review provides a comprehensive state-of-the-art overview (Table 1) of nanodelivery systems reaching the posterior portion of the eye through topical application. Forty studies were revised, and, to the best of our knowledge, they represent the main works using solely the topical route of administration to reach the posterior segment of the eye. The key criterion for selecting the studies included in the revision was the in vivo assessment in animal models (regardless of the animal) that measurably confirmed the detection of therapeutic compounds in posterior eye tissues. It should be noted, however, that rodents, which are commonly used to study topical drug delivery to the eye, because they are readily available and similar to humans in many aspects, still have anatomical differences. Their smaller eyes, thicker corneas, and faster tear turnover rates affect drug penetration and distribution [33,34]. Additionally, discrepancies in ocular surface composition and vitreous humor volume pose challenges in extrapolating findings in rodents to humans [35]. Additionally, alternative models, such as rabbits, pigs, or non-human primates, also presented in Table 1, may better mimic human ocular anatomy and physiology for certain aspects of ocular drug delivery research. Studies focusing solely on in vitro assays or alternative administration routes were excluded from Table 1. 2. Ocular barriers encountered upon topical ophthalmic therapeutic administration When considering topical ophthalmic delivery, therapeutic agents can take one of two major permeation routes, with several elimination routes to systemic circulation (Fig. 2) [29,76]. The first is the corneal route, which includes the tear film, cornea, anterior chamber, lens (therapeutics can cross it or go around it by possible parallel diffusion routes), posterior chamber, vitreous chamber, and retina. The second is the non-corneal (or conjunctival) route and comprises the tear film, conjunctiva, sclera, choroid, and retina [76]. Both the tear film and the retina are common structures to each route. The subsequent sections will provide a detailed review of the various eye compartments, their barriers, and possible strategies to successfully overcome them. 2.1. Barriers to therapeutic absorption common in corneal and conjunctival routes Fig. 3 depicts the barriers encountered during therapeutic absorption via the corneal and the conjunctival route, which are then explained in the text. 2.1.1. Tear film turnover The precorneal region represents the outermost eye barrier and is the first one to be surpassed after topical therapeutic administration. In this region, the presence of dynamic barriers, such as tear turnover or blinking mechanisms (Fig. 2), cause a partial drug clearance that ultimately results in poor drug bioavailability. In addition, tear film selectivity also compromises the delivery and penetration of therapeutic agents along mucosal surfaces [77]. The tear film (pH≈7.4) has a thickness of approximately 8 µm and is constituted by a lipid layer and a muco-aqueous layer (Fig. 3) [24,78]. The lipid layer is the first line of defense against foreign agents and is mainly composed of a mixture of lipids (triglycerides, cholesterol, free fatty acids, waxes, and others) secreted by the Meibomian, Zeiss, and Moll glands [24,27]. The lipophilic environment within this area limits the hydrophilic drugs’ diffusion to the corneal interface and prevents the evaporation of the lachrymal fluid. Subsequently, the muco-aqueous layer helps to moisten and hydrate the eye surface, accounting about 90% of the overall volume of the tear film [24]. The fluid, mainly composed of monovalent and divalent inorganic ions such as Na + , K + , Cl − , HCO 3 − , and proteins, is secreted by the lachrymal gland [24]. Finally, mucus is a biological barrier that covers and protects exposed surfaces of the body [79,80]. This hydrophilic gel, rich in negatively charged mucins, maintains epithelial hydration but also has a selective permeability that allows the exchange of water, nutrients, and gases with the underlying epithelium while restricting the diffusion of pathogens and other particles (for detailed information, see section 2.3) [80,81]. 2.1.2. Blood-retinal barrier (BRB) The blood-retinal barrier (BRB) is a highly specialized barrier with selective permeability formed by an inner (iBRB) and outer (oBRB) layer [26]. The retinal capillary endothelial (RCE) cells and the retinal pigmented epithelium (RPE) constitute the iBRB and oBRB, respectively (Fig. 3) [26,27]. In both layers, the cells are closely associated by tight junctions that restrict the penetration of molecules to intraocular tissues M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 4 Table 1 State-of-the-art overview of successful ocular drug delivery systems reaching the posterior segment of the eye following topical application. Nanocarrier Topical vehicle Composition Therapeutic agent Physicochemical parameters Strategies to reach posterior eye segment Experimental model Ref. Liposomes Eye drops •PEG15H •PEG-12 glyceryl dimyristate •BAC TA (Corticosteroid) Size: 187.8 nm PDI: 0.6 ζ Potential: +0.554 mV E.E.: 35% •Coating with PEG15H •BAC: −Penetration enhancer •Close to neutral surface charge •Reduced size (<300 nm) •In vitro: HCF cell line •In vivo: rabbits [36] Liposomes Eye drops •SPC •CHOL •CHS TA (Corticosteroid) Size: 135.46 ±4.49 nm PDI: 0.21 ±0.03 ζ Potential: +17.98 ± 3.21 mV E.E.: 90.66 ±3.21% •Coating with CHS: −Overall cationic charge −Mucoadhesive properties −Hydrophilic permeation enhancer •Reduced size (<300 nm) •In vitro: HCEC and ARPE-19 cell lines •In vivo: mice [37] Liposomes Eye drops •SPC •CHOL •CHS TA (Corticosteroid) Size: 176 nm PDI: N.D. ζ Potential: +41.1 mV E.E.: 74% •Coating with CHS: −Overall cationic charge −Mucoadhesive properties −Hydrophilic permeation enhancer •Reduced size (<300 nm) •In vivo: rats [38] Liposomes Eye drops •EPC •CHOL EDV (Antioxidant) Size: 92.6 ±1.5 nm PDI: ζ Potential: +7.4 ± 0.4 mV E.E.: 41.4 ±0.3% •Close to neutral surface charge •Reduced size (<300 nm) •In vitro: HCEC and NHC cell lines •In vivo: Mice [39] Liposomes Eye drops •DSPC or EPC •DCP or SA •CHOL Coumarin-6 (Fluorescent probe) Size: 114.0–561.0 nm PDI: N.D. ζ Potential: −76.9 to +25.9 mV E.E.: N.D. •DCP: −Negative charge •SA: −Overall cationic charge −Mucoadhesive properties •DSPC: −Rigid lipid (T m ≈55 ◦C) diffuses better through than fluid lipids (EPC) •Reduced size (<300 nm) •In vivo: rats, rabbits and monkeys [40] Liposomes Eye drops •EPC •DCP •CHOL •PLL Coumarin-6 (Fluorescent probe) Unmodified Liposomes:Size: 94.6 nm PDI: 0.064 ζ Potential: −40.2 mV E.E.: N.D. PLL-modified liposomes:Size: 97.2 to 286.3 nm PDI: 0.068 to 0.726 ζ Potential: −39.5 to +15.7 mV •PLL: −Cationic polymer −Mucoadhesive and mucopenetrating properties depending on [PLL] concentration •Reduced size (<300 nm) •In vivo: mice [41] Liposomes Eye drops •TMAG •DLPC •DOPE •DC-CHOL pDNA for β-galactosidase (Plasmid vector) N.D. •TMAG: −Overall cationic charge −Mucoadhesive properties •DOPE: −Fusogenic properties •In vivo: rats [42] Liposomes Eye drops •DSPC •CHOL •PVA or PVA-R DF (Anti-inflammatory) Size: 176.7 nm PDI: 0.037 ζ Potential: −0.5 mV E.E.: 98.9% •PVA-R: −Mucoadhesive properties •Reduced size (<300 nm) •In vivo: rabbits [43] Liposomes Eye drops •EPC •Brain PS •CHOL •Vit E •Annexin-A5 BVZ (Anti-VEGF) Size: 163 ±73 nm PDI: 0.203 ζ Potential: −7.2 ± 0.6 mV E.E.: 25% •EPC and Brain PS: −Confer negative charge •AnnexinA5: −Corneal permeation enhancer •Reduced size (<300 nm) •In vitro: HCE cell line •In vivo: rats and rabbits [44] Liposomes Eye drops •DPPC •DOPS •CHOL •Annexin-A5 TGF-β1 (Polypeptide member of the TGF-β superfamily of cytokines) Size: 157 nm PDI: 0.176 ζ Potential: −28.83 ± 0.9 mV E.E.: 30% •DOPS: −Confers negative charge •AnnexinA5: −Corneal permeation enhancer •Reduced size (<300 nm) •In vivo: rabbits [45] Solid lipid nanoparticles Eye drops •SA •PC •STC TBM (Antibiotic) Size: 80.01 ±11.10 nm PDI: 0.155 ±0.03 ζ Potential: −25.7 ± 0.20 mV E.E.: 2.5% w/w •SA: −Confers an overall negative charge •STC: −Penetration enhancer •Reduced size (<300 nm) •In vivo: rabbits [46] (continued on next page) M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 5 Table 1 (continued) Nanocarrier Topical vehicle Composition Therapeutic agent Physicochemical parameters Strategies to reach posterior eye segment Experimental model Ref. Solid lipid nanoparticles Eye drops •Compritol®888 ATO •HSPC •Tween®80 •PEG-600 KTZ (Antifungal) Size: 126.35 ±2.2 nm PDI: 0.28 ±0.02 ζ Potential: −3.19 mV E.E.: 70.19 ±1.94% •Coating with PEG-600: −Hydrophilic and mucopenetrating −P-gp efflux inhibitors •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •Reduced size (<300 nm) •In vitro: ARPE-19 and RCE cell lines •In vivo: rabbits [47] Solid lipid nanoparticles Eye drops •Compritol®888 ATO •P188 •Tween®80 •Glycerin •CHS IN (Anti-inflammatory) Size: 265 ±8 nm PDI: 0.30 ζ Potential: +27 ± 1.2 mV E.E.: 91.5 ±3.2% •Coating with CHS: −Overall cationic charge −Mucoadhesive properties −Hydrophilic permeation enhancer •P188: −Hydrophilic and mucopenetrating •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •Reduced size (<300 nm) •In vitro: excised corneas and scleral tissue with retinal pigmented epithelium from rabbits •In vivo: rabbits [48] Solid lipid nanoparticles •Compritol®888 ATO •PEG400 •HSPC •P188 ATS (Statins) Size: 256.3 ±10.5 nm PDI: 0.26 ±0.02 ζ Potential: 2.65 mV E.E.: 73.1 ±1.52% •PEG 400 and P188: −Hydrophilic and mucopenetrating •PEG 400: −Inhibits P-gp efflux pumps •Neutral surface charge •Reduced size (<300 nm) •In vitro: HCLE, R28, ARPE-19 and RCE cell lines •In vivo: rabbits [49] Solid lipid nanoparticles Eye drops & gel SLN composition: •Compritol®888 ATO •GMS •P188 •Tween®80 TA (Corticosteroid) Size: 187.5 ±1.8 nm PDI: 0.35 ±0.09 ζ Potential: –33 ±2.5 mV E.E.: 95.1 ±1.3% •Gelling agents −Increase corneal residence time •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •P188: −Hydrophilic and mucopenetrating •Overall negative charge •Reduced size (<300 nm) •In vitro: isolated rabbit corneas •In vivo: rabbits [50] Nanostructured lipid carriers Eye drops •Compritol®888 ATO •Miglyol® 812 •P188 PEA (Anti-inflammatory) Size: 264.5 ±0.19 nm PDI: 0.200 ±0.035 ζ Potential: −37.1 ± 0.02 mV E.E.: 82.3 ±0.82% •Overall negative charge •P188: −Hydrophilic and mucopenetrating •Reduced size (<300 nm) •In vivo: rats [51] Nanostructured lipid carriers Eye drops •Compritol®888 ATO •Miglyol® 812 •P188 PEA (Anti-inflammatory) Size: 208.6 ±10.2 nm PDI: 0.18 ζ Potential: >−20 mV E.E.: N.D. •Overall negative charge •P188: −Hydrophilic and mucopenetrating •Reduced size (<300 nm) •In vivo: rabbits [52] Nanostructured lipid carriers Eye drops •Compritol®888 ATO •Miglyol® 812 •P188 •Tween® 80 •Propylene Glycol IN (Anti-inflammatory) Size: 227 ±11 nm PDI: 0.23 ζ Potential: −12.2 ± 2.3 mV E.E.: 99.8 ±0.2% •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •P188: −Hydrophilic and mucopenetrating •Reduced size (<300 nm) •In vivo: rabbits [48] Nanostructured lipid carriers Eye drops •Precirol®ATO5 •P188 •Squalene® •MO TA (Corticosteroid) Size: 173.30 ±0.32 nm PDI: 0.10 ±0.02 ζ Potential: −46.70 ± 0.91 mV E.E.: 94.82 ±1.12% •MO: −Fusogenic properties •P188: −Hydrophilic and mucopenetrating •Reduced size (<300 nm) •In vivo: mice [53] Nanostructured lipid carriers Eye drops •Precirol®ATO5 •CO •mPEG-2000DSPE •P188 •Tween® 80 AmB (Antifungal) Size: 218 ±5 nm PDI: 0.3 ±0.02 ζ Potential: −50 to −55 mV E.E.: 92.7 ±2.5% •mPEG-2000-DSPE and P188: −Hydrophilic and mucopenetrating •mPEG-2000-DSPE: −Inhibits P-gp efflux pumps •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •Reduced size (<300 nm) •In vitro: ARPE-19 cell line •In vivo: rabbits [54] Emulsomes Eye drops •DPPC •GMS •CHOL TA (Corticosteroid) Size: 131.17 ±3.17 nm PDI: 0.198 ±0.021 ζ Potential: −24.2 ± •Overall negative surface charge •Reduced size (<300 nm) •In vitro: SIRC cell line •In vivo: mice and rabbits [55] (continued on next page) M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 6 Table 1 (continued) Nanocarrier Topical vehicle Composition Therapeutic agent Physicochemical parameters Strategies to reach posterior eye segment Experimental model Ref. 2.12 mV E.E.: 71.56 ±4.19% Nanoemulsion In situ gel •MCT •EPC •Vit E •P188 •Penetratin Lutein (Carotenoid) Size: 109.8 nm PDI: 0.079 ±0.008 ζ Potential: +16.9 mV E.E.: N.D. •In situ gel: −Prolongs the residence time of P-NE at the ocular surface •Penetratin: −CPP that acts as a permeation enhancer, −Confers an overall cationic charge •P188: −Hydrophilic and mucopenetrating •Reduced size (<300 nm) •In vitro: ARPE-19 cell line •In vivo: rats, mice and rabbits [56] Nanoemulsion Eye drops •EPC or HSPC •MCT •CO •DCP or STE •CHS or P407 Coumarin-6 (Fluorescent probe) Unmodified Size: 89.25 nm PDI: 0.123 ζ Potential: −34.6 ± 7.46 mV CS-modified Size: 94.49 nm PDI: 0.104 ζ Potential: −14.9 ± 6.10 mV P407-modified Size: 110.6 nm PDI: 0.194 ζ Potential: −42.7 ± 8.25 mV E.E.: ≈98% •STE: −Overall cationic charge −Mucoadhesive properties •Coating with CHS: −Overall cationic charge −Mucoadhesive properties −Hydrophilic permeation enhancer •P407: −Gelling agent −Neutral charge •Reduced size (<300 nm) •In vivo: mice [57] Dendrimers Eye drops •PAMAM •Cyclic RGD •Penetratin •PEG N.D. Size: 19.16 ±0.41 nm PDI: N.D. ζ Potential: +6.74 ± 0.37 mV E.E.: N.D. •Penetratin: −CPP that acts as a permeation enhancer, −Confers an overall cationic charge •RGD: −High specificity towards integrin αν β3 (involved in neovascularization) •Coating with PEG: −Hydrophilic and mucopenetrating −P-gp efflux inhibitors •Reduced size (<300 nm) •In vitro: HCE, HUVEC and NHC cell lines •In vivo: mice [58] Dendrimers Eye drops •PAMAM-COOH DEX (Corticosteroid) Size: 131.20 ±19.43 nm PDI: N.D. ζ Potential: −52.23 ± 2.54 mV E.E.: 100% •PAMAM-COOH: −Overall negative charge •Reduced size (<300 nm) •In vitro: ARPE-19 cell line •In vivo: rats [59] Dendrimers Eye drops •PAMAM •Penetratin pRFP (Fluorescent plasmid) Size: 154.8 ±8.9 nm PDI: 0.167 ±0.007 ζ Potential: +29.9 ± 1.0 mV E.E.: N.D. •Penetratin: −CPP that acts as a permeation enhancer, −Confers an overall cationic charge •Reduced size (<300 nm) •In vitro: NHC and SDHCEC cell lines •In vivo: mice [60] Cyclodextrin Eye drops •(2hydroxypropyl)- β-cyclodextrin •Hypromellose •Caffeine AXT (RTKi) E.E.: 8.494 ±132.1% (w/v%) •β-cyclodextrin: −Hydrophilic −Penetration enhancer •In vivo: rabbits and non-human primates [61] Cyclodextrin Eye drops •γ-cyclodextrin DEX (Corticosteroid) Size: 20.4 ±10.3 µm •γ-cyclodextrin: −Hydrophilic −Penetration enhancer •Reduced size (<300 nm) •In vivo: rabbits [62] Cyclodextrin Eye drops •γ-cyclodextrin IRB, CAN (Antagonists of angiotensin II receptor) N.D. •γ-cyclodextrin: −Hydrophilic −Penetration enhancer •In vivo: rabbits [63] (continued on next page) M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 7 Table 1 (continued) Nanocarrier Topical vehicle Composition Therapeutic agent Physicochemical parameters Strategies to reach posterior eye segment Experimental model Ref. Polymeric micelles Eye drops •PEG •PPG •PCL AFL (VEGF-A) Size: 64.5 nm PDI: N.D. ζ Potential: N.D. E.E.: 47.3% •Coating with PEG: −Hydrophilic and mucopenetrating −P-gp efflux inhibitors •Reduced size (<300 nm) •In vitro: ARPE-19 cell line •In vivo: mice [64] Polymeric micelles Eye drops •MPEG-hexPLA CsA (Immuno suppressant) Size: 54 ±1 nm PDI: 0.229 ±0.008 ζ Potential: N.D. E.E.: 4.9 ±0.2 mg/mL •Coating with MPEG: −Hydrophilic and mucopenetrating −P-gp efflux inhibitors •Reduced size (<300 nm) •In vivo: rats [65] Polymeric micelles Eye drops •P40S •Tween® 80 DEX (Corticosteroid) Size: 14.5 ±0.4 nm PDI: N.D. ζ Potential: 0.23 mV E.E.: 100% •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •P40S: −Hydrophilic and mucopenetrating −Inhibits P-gp efflux pumps •Close to neutral surface charge •Reduced size (<300 nm) •In vivo: rabbits [66] Polymeric micelles Eye drops •Vit E TPGS •Oc-40 •Povidone K 90 RAP (Antibiotic) Size: 10.84 ±0.11 nm PDI: 0.05 ζ Potential: −0.789 mV E.E.: 100 ±1.2% •Vitamin E TPGS: −Absorption enhancer by inhibiting P-gp efflux pumps •Povidone K 90: −Enhances formulation viscosity which increases retention time at the ocular surface •Hydrophilic corona of nanomicelles: −Can use scleral aqueous channels/pores and minimize washout into systemic circulation •Reduced size (<300 nm) •In vitro: D407 and rPCEC cell lines •In vivo: rabbits [67] Polymeric nanoparticles Eye drops •PLGA •P188 FMT (Corticosteroids) Size: 149.1 ±3.5 nm PDI: 0.079 ±0.008 ζ Potential: −34.3 ± 1.6 mV E.E.: 99.8 ±0.2% •PLGA: −Overall negative charge •P188: −Hydrophilic and mucopenetrating •Reduced size (<300 nm) •In vitro: HET-CAM •In vivo: pigs [68] Polymeric nanoparticles Eye drops •PLGA •Surface: CHS, GCHS or Tween® 80 Coumarin-6 (Fluorescent probe) Unmodified Size: 224.5 nm PDI: 0.068 ζ Potential: −41.3 mVE.E.: N.D. CS , GCS and Tween® 80 Size: 332.7, 518.6 and 240.7 nm PDI: 0.339, 0.296 and 0.129 ζ Potential: −9.34, +39.9, −44.6 mV E.E.: N.D. •CHS and GCHS: −Overall cationic charge −Mucoadhesive properties −Hydrophilic permeation enhancer •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •Reduced size (<300 nm) •In vivo: mice [69] Polymeric nanoparticles Eye drops •CHS •HA EPOβ Size: 289 ±3 nm PDI: 0.126 ±0.085 ζ Potential: 39 ±1 mV E.E.: 38.4 ±0.3% •Coating with CHS: −Overall cationic charge −Mucoadhesive properties −Hydrophilic permeation enhancer •HA: −Affinity to CD44 cell receptors •Reduced size (<300 nm) •In vitro: ARPE-19 and HaCaT cells •In vivo: rats [70] Polymeric nanoparticles Eye drops & In situ gel NPs composition: •PLGA •Tween® 80 RLZ(Benzothiazole) Size: 148.2 ±1.4 nm PDI: 0.116 ±0.011 ζ Potential: −30.0 ± 0.6 mV E.E.: 94.2 ±0.8% •PLGA: −Overall negative charge •Tween® 80: −Penetration enhancer −P-gp efflux inhibitors •Reduced size (<300 nm) •In vivo: mice [71] BSA nanoparticles Eye drops •BSA •HA APA (RTKi) Size: 222.2 ±3.56 nm PDI: 0.22 ζ Potential: −37.3 ± 1.8 mV •HA: −Overall negative chargeAffinity to CD44 cell •In vitro: RCE cell line •In vivo: rats [72] (continued on next page) M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 8 (1–2%) and are responsible for a poor therapeutic outcome in posterior eye disorders [82,83]. Furthermore, the expression of efflux transporters such as P-gp also represents an obstacle to therapeutic delivery across the BRB, given the rapid drug clearance from the extravascular space (Fig. 2) [84,85]. The iBRB regulates the microenvironment of neuroretina by blocking the diffusion of hydrophilic compounds across retinal capillaries [82]. Furthermore, the iBRB is covered by an underlying layer of Müller cells, astrocytes, and pericytes. These cells can sense variations in the extracellular fluid and relaying this information as signals to the RCE cells [82,86]. The oBRB is composed of a monolayer of RPE cells located atop the iBRB that restricts the diffusion of solutes from the sclera/choroid to the retina [86]. Given the limited permeability of the intercellular junction complex surrounding endothelial and epithelial cells, therapeutics are more likely to diffuse transcellularly across the BRB [87,88]. 2.2. Barriers to therapeutic absorption via the corneal route 2.2.1. Corneal barriers The human cornea is the major barrier encountered upon topical therapeutic administration and includes three main layers of alternating polarity: the corneal epithelium, stroma, and endothelium, separated by Bowman’s and Descemet’s membranes, respectively (Fig. 3) [89]. Recently, a fourth layer, located among the Descemet’s membrane and the stroma, was identified and termed as the Dua’s layer (Fig. 3) [90]. At this level, the epithelium of the cornea is the primary barrier because it forms intercellular tight junctions around the superficial epithelial cells that act as selective barriers for small molecules and limit the diffusion of macromolecules and hydrophilic compounds [3,91]. The polarity of the compound, and its molecular weight, determine its transport across the cornea. Depending upon the partition coefficient (logP), the therapeutic agent can diffuse via paracellular or transcellular route. logP is an indicator of drug distribution between aqueous and lipid phases [92]. Additionally, logP is a reliable tool to predict drug absorption, distribution, metabolism, and elimination processes, as well to assess their toxic and/or therapeutic effects [92]. Thus, lipophilic therapeutic agents (logP >0) will likely benefit from the transcellular pathway to diffuse across the epithelium of the cornea, while small hydrophilic therapeutic agents (logP <0) would benefit the paracellular route [29]. Table 1 (continued) Nanocarrier Topical vehicle Composition Therapeutic agent Physicochemical parameters Strategies to reach posterior eye segment Experimental model Ref. E.E.: 69 ±1% receptors •Reduced size (<300 nm) MPP Eye drops •P407 LE & KAL821 (Corticosteroid & RTKi) LE-MPP & KAL-821MPP Size: 240 & 160 nm PDI: N.D. ζ Potential: Neutral E.E.: N.D. •P407: −Gelling agent −Neutral charge •Reduced size (<300 nm) •In vivo: rabbits and mini-pigs [73] Nanocomposite (Liposome@LDH) Eye drops •HSPC •CHOL •Pristine LDH •GS DEXP (Corticosteroid) Size: 187.7 ±7.9 nm PDI: 0.241 ζ Potential: +24.33 ± 2.56 mV E.E.: 69 ±1% •LDH: −Overall cationic charge −Mucoadhesive properties •Clathrin-mediated endocytosis •Active transport by PepT-1 •Reduced size (<300 nm) •In vitro: HCEC and NHC cell lines •In vivo: rabbits [74] Gold Nanoparticles Eye drops •HAuCl 4 •HA N.D. Size: 15–20 nm PDI: N.D. ζ Potential: N.D. E.E.: N.D. •HA: −Overall negative chargeAffinity to CD44 cell receptors •Reduced size (<300 nm) •In vivo: mice [75] AFL: Aflibercept; AmB: Amphotericin B; APA: Apatinib; ARPE-19: Arising retinal pigment epithelia cell line derived from the normal eyes of a 19-year-old male; ATS: Atorvastatin; AXT: Axitinib; BAC: Benzalkonium chloride; BSA: Bovine serum albumin; BVZ: Bevacizumab; CAN: Candesartan; CHOL: Cholesterol; CHS: Chitosan; CO: Castor oil; Compritol®888 ATO: blend of different esters of behenic acid with glycerol or glyceryl behenate; CPP: Cell penetrating peptide; CsA: Cyclosporin A; D407: Human retinal pigment epithelial cells; DCP: Dicetylphosphate; DEX: Dexamethasone; DEXP: Dexamethasone disodium phosphate; DF: Diclofenac; DLPC: 1,2dilauroyl-sn-glycero-3-phosphocholine; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DOPS: 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (sodium salt); DPPC: 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine or Dipalmitoyl phosphatidylcholine or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine or 1,2-Dipalmitoyl-3-snphosphatidylcholine or 1,2-Dipalmitoyl-L-lecithin; DSPC: 1,2-distearoyl-sn-glycero-3-phosphocholine or 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine; DSPEPEG2000: Conjugate of 1,2distearoyl sn-glycero-3-phosphoethanolamine and polyethylene glycol (2000) monostearate; EDV: Edaravone; EE: Encapsulation efficiency; EP: Epalrestat; EPC: egg phosphatidylcholine; EPOβ: Epoetin beta; FMT: Fluorometholone; GCHS: Glycol chitosan; GS: glycylsarcosine; HA: Hyaluronic acid; HAuCl 4 : gold (III) chloride hydrate; HCEC: Human corneal epithelial cells; HCF: Primary human corneal fibroblasts; HCLE: Human cornea limbal epitelial; HET-CAM: Hen’s egg-chorioallantoic membrane test; HSPC: Hydrogenated soybean phosphatidylcholine or Phospholipon® 90H or Lα -phosphatidylcholine, hydrogenated (Soy); HUVEC: Human umbilical vein endothelial cells; IN: Indomethacin; IRB: Irbesartan; KTZ: Ketoconazole; LE: Loteprednol etabonate; LDH: Layered Double Hydroxides; Miglyol®812: caprylic/capric triglycerides; mPEG-hexPLA: Methoxy poly(ethylene) glycol-hexylsubstituted poly(lactides); MPP: Mucus penetrating particles; N.D.: Not defined; NHC: Human conjunctival epithelial cells; NPs: Nanoparticles; Oc-40: Octoxynol-40; P188: Poloxamer 188 or Pluronic F68® or Kolliphor P188® or Lutrol F68®; P407: Poloxamer 407 or Pluronic F-127; P40S: Polyoxyl 40 stearate; PAMAM: Poly(amidoamine); PC: 1,2-diacyl-sn-glycero-3-phosphocholine or Phosphatidylcholine or Diacylphosphatidylcholine or lecithin or Epikuron® 200 or Phospholipon®90 G; PCL: Polycaprolactone; PDI: Polidispersity index; pDNA: Plasmid DNA; PEG15H: Polyethylene glycol (15)-hydroxystearate or Macrogol 15 hydroxystearate or Polyoxyl 15 Hydroxystearate or Solutol HS® 15 or Kolliphor® HS15 or PEG-660 stearate; PEG400: Polyethylene glycol (400) monostearate; PEA: Palmitoylethanolamide; PEG: poly(ethyleneglycol); PEG2000-SA: poly(ethyleneglycol) monostearate; PLL: Poly-L-Lysine; PPG: Poly(propylene glycol); pRFP: Red fluorescente protein plasmid; PVA: Poly(vinyl alcohol); PVA-R: Poly(vinyl alcohol) derivatives bearing a hydrophobic anchor (C16H33–S–) at the terminal of the molecule; Precirol®5 ATO: Glyceryl palmitostearate; Tween® 80: Polysorbate 80; PLGA: Poly(lacticco-glycolic acid); R28: Retinal neuronal; RAP: Rapamycin; RCE: Rabbit corneal epithelial cell lines; rPCECs: Rabbit primary corneal epithelial cells; RTKi: Receptor tyrosine kinase inhibitor; SA: Stearic acid or octadecanoic acid or n-Octadecanoic acid; SDHCEC: Spontaneously derived human corneal epithelial cells; SIRC: Statens Seruminstitut Rabbit Corneal cell line; SPC: soybean phosphatidylcholine; STC: Sodium taurocholate; STE: stearylamine; TA: Triamcinolone acetonide; TBM: Tobramycin; TGF-β: Transforming growth factor beta; Tm: Phase transition temperature; TMAG: N-(alpha-trimethylammonioacetyl)-didodecyl-D-glutamate; VEGF: Vascular endothelial growth factor; Vit E: Vitamin E or Tocopherol or α -tocopherol; Vit E TPGS: Vitamin E tocopherol polyethylene glycol succinate. M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 9 2.2.2. Anterior and posterior chambers The anterior eye chamber, situated between the cornea and the iris, and the posterior eye chamber, placed between the ciliary body and iris, are filled with aqueous humor (≈200-300 μ L total volume) [76,88]. Despite its reduced protein content, aqueous humor is chemically comparable to blood plasma [88]. The main role of this water-like fluid is to grant nutrients and antioxidants to the lens and cornea, but it also aids in the preservation of the IOP and the eye’s spherical shape [88,93]. The epithelial cells of the ciliary body continuously secrete aqueous humor, which flows from the posterior to the anterior chamber and is subsequently drained via the trabecular meshwork into Schlemm’s canal. It then exits the eye by the uveoscleral pathway and enters the Fig. 2. Graphical representation of the two principal topical ophthalmic routes for therapeutics absorption and potential parallel diffusion courses. The primary pathways by which therapeutic agents enter the circulatory system are also shown. Fig. 3. Graphical illustration of the primary ocular barriers encountered upon topical ophthalmic therapeutic delivery in each major permeation route. M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 16 region and significantly improving their bioavailability. The developed system complies with such features and seems to extend the residence time of lutein and its penetration through the different tissues and fluids of the eye [56]. In another study, triamcinolone acetonide-loaded SLN (TA-SLN) were included in in-situ gels (IG-TA-SLN) to enhance TA delivery to deeper ocular tissues [50]. In vivo studies on transcorneal permeability and TA biodistribution revealed that IG-TA-SLN increased permeability through rabbit corneas and was able to deliver higher TA concentrations to both anterior and posterior tissues when compared to TA-SLN suspension [50]. Besides hydrogels, the incorporation of therapeutic agents in CL has been also gaining attention for the treatment of ocular conditions [116]. Although primarily designed to correct refractive errors, hydrophilic CL are currently seen as promising therapeutic devices. The first generation of CL was made of poly (methyl methacrylate) (PMMA), a non-foldable rigid material with poor oxygen permeability and wettability properties [137]. These lenses did not provide a comfortable user experience and were replaced for rigid gas-permeable contact lenses (RGP) and soft contact lenses (sCL) [137]. Besides higher flexibility, sCL have better hydrophilic and bioavailability properties and may be composed of hydrogel or silicone-hydrogel [137,138]. Therapeutic agents can be included within CL matrix by three main processes: (i) soaking; (ii) molecular imprinting; and (iii) direct incorporation of drug-loaded nanocarriers [126]. The first method is the most affordable and consists in soaking the lens in an enriched pharmaceutic solution [138]. Despite its simplicity, the soaking method is not efficient and the incorporated molecules are released within 1–3 h [137]. Molecular imprinting is more difficult and involves polymeric modification to imprint in it certain morphological changes that will increase the affinity towards therapeutic molecules and, ultimately, improve the loading Fig. 7. Compilation of in vivo studies using theranostic devices to diagnose and treat ocular conditions in the anterior and posterior segments of the eye. Section I (A)- (D) shows a wireless theranostic CL able to monitor glucose levels in rabbit eyes’ tear film and deliver therapeutic concentrations of genistein to the retina. (A) Schematic representation of the theranostic smart CL; (B) Demonstrates the ability of smart CL to selectively release genistein from the drug reservoirs after applying an electrical potential. Changes in the current of the smart CL and evidence of genistein release in a pulsatile manner. (C) Real-time monitoring of glucose levels in diabetic rabbits using smart CL. Glucose was measured in the blood and the tear (i) after injection of insulin and anesthesia and (ii) after wearing the smart CL, the sensor detected an increase of glucose concentration in the tear (30.53 mg dl −1 , tear glucose), and then it decreased (16.72 mg dl −1 ) due to the insulin effect, which was in line with the blood glucose levels determined by a glucometer. The blood glucose level was measured every 5 min with a commercial glucometer. (D) Absorption of genistein in vivo. Fluorescence images of cryo-sectioned cornea, sclera, and retina of rabbits wearing genistein-loaded smart CL (top row) and smart CL without genistein. Scale bar, 0.1 mm. Section II (A)-(C) displays the binding affinity of silicon nanoparticles (SiNPs) and cyclo-(Arg-Gly-Asp-d-Tyr-Cys) (c-(RGDyC))- conjugated SiNPs (SiNPs-RGD) to angiogenic blood vessels in mice corneas. (A) Schematic representation of the experiment. (B) Corneal neovascularization progress following NaOH injury burn from day 1 to day 7. Scale bar, 5 mm. (C) Fluorescence images of mice corneas 4 h after intravenous injection of SiNP (upper row) and SiNPs-RGD (lower row). The binding of SiNP/SiNPs-RGD to angiogenic blood vessels was monitored in vivo. Scale bar, 25 μ m. Section III (A)-(B) demonstrates a smart CL capable of controlling IOP in glaucoma and releasing timolol after electrical triggering on alternative days over a period of 5 days. (A) Fully assembled theranostic smart CL in rabbit’s eye. Scale bar, 5.5 mm. (B) IOP levels on day 1 were high (above 22 mmHg), and timolol was released leading to IOP reduction to the normal range values. On day 3, IOP levels were still above the normal range and timolol was released again and decreased IOP to near the normal range. The IOP was within the normal range on day 5 and no timolol was released from the gold channels of smart CL. Reproduced with permission: [144,145,147]. Copyright © 2020, American Association for the Advancement of Science under CC BY-NC 4.0 license; Copyright © 2018, American Chemical Society; Copyright © 2022, Springer Nature under CC BY 4.0 license. M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 17 capacity of CL [138]. Throughout this process, functional monomers are used as molds of therapeutic agents [116,138]. Despite its great potential, the complex synthesis process behind molecular imprinting makes it a non-affordable and time-consuming option [137]. In order to surpass these constraints, the incorporation of therapeutic-loaded nanocarriers within the polymeric matrix of CL demonstrated promising results and higher adherence [126]. In fact, similarly to hydrogels, therapeuticloaded nanocarriers are retained within the lenses for higher periods and, consequently, achieve a more sustained release over time [116]. In a recent work, eluting CL loaded with a dexamethasone (DEX)-polymer film (CL-DEX) were developed to prevent inflammation in the posterior segment of the eye [139]. The findings indicated that, as compared to eye drops, CL promoted higher DEX concentrations (≈200x) in the retina of rabbits and lowered DEX systemic exposure [139] Furthermore, CL-DEX blocked retinal vascular leakage induced by intravitreal injection of VEGF [139]. Finally, in vivo biocompatibility studies in rabbits assured CL-DEX safety after a four-week repeated dose [139]. 4. Theranostic devices designed for ocular diseases Theranostic is a cornerstone of nanomedicine that focuses efforts on developing strategies that combine, simultaneously, diagnostic and therapeutic tools [140]. Hence, theranostic devices may function as drug delivery platforms while acting as bioimaging agents [141,142]. Offering the capacity to provide a diagnosis before to, after, or during therapy presents the prospect for tailored medicine, representing a significant advancement in clinical practice [143]. Undoubtedly, there has been a substantial rise in the investigation and advancement of theranostic methodologies, with the majority of systems depending on the integration of inorganic and organic constituents [142]. Nevertheless, the potentialities of theranostic in ARRD and its topical application are still poorly exploited. Here, we highlight the study of Keum et al. [144] focused on the development of wireless theranostic CL for the diagnosis and treatment of diabetic retinopathy (Fig. 7-I). This device provides real-time monitoring of glucose tear levels in the of rabbit eyes and subsequent therapeutic delivery of genistein [144]. It was observed that the therapeutic effect of genistein delivered through CL to the retina was comparable to Avastin delivered via intravitreal injection in diabetic retinopathy [144]. As so, smart CL proved to be feasible theranostic tools for continuous diabetic diagnosis and treatment [144]. In a different study, a theranostic smart CL capable of both monitoring IOP and delivering on-demand therapeutic treatment for glaucoma management was developed (Fig. 7-III) [145]. The CL is constituted with a highly sensitive IOP sensor based on gold hollow nanowires, a flexible drug delivery system (DDS), wireless power and communication systems, and an application-specific integrated circuit (ASIC) chip [145]. The in vivo results in glaucoma-induced rabbits demonstrated that the smart CL’s flexible DDS allowed timolol delivery and was effective in controlling IOP to the normal range values and preventing glaucoma progression [145]. Topical strategies for other diseases (e.g., infectious, or inflammatory) affecting the anterior eye region, have already been reported. For example, CL with a hybrid surface were used as theranostic devices [146]. Surface functionalization was attained using anti-interleukin-1 α (IL-1 α ) antibodies as biomarkers for detection of IL-1 α [146]. During corneal herpes simplex virus (HSV-1) infection, IL-1 α is upregulated and inflammation can be detected through the capture of IL-1 α [146]. Furthermore, poly(sodium 4-styrenesulfonate) (PSS) was the innermost coating layer of CL, acting as an antiviral agent [146]. PSS demonstrated effective antiviral activity against HSV-1, probably by inhibiting virus adsorption onto cell surface receptors, thus preventing viral entry [146]. Tang and co-workers [147], developed silicon nanoparticles (SiNPs) to be used as theranostic agents for imaging and treatment of eye neovascularization (Fig. 7-II). Specifically, SiNPs were decorated with cyclo-(Arg-Gly-Asp-D-Tyr-Cys) (c-(RGDyC)) integrins that feature high binding affinity to human retinal microvascular endothelial cells (HRMECs) tube formation [147]. As a result, SiNPs-RGD complex was able to detect angiogenic endothelial cells in vitro while showing potent antiangiogenic effect [147]. Salem et al. [148] used liposomes containing flucytosine capped with gold nanoparticles as a dual-function system for monitorization and treatment. Flucytosine-loaded liposomes were topically applied to treat fungal intraocular endophthalmitis while gold nanoparticles acted as contrasting agents that enabled the tracking of the antifungal agent [148]. It was reported that the developed formulation permeates into intraocular tissues and, consequently, deliver significant amounts of flucytosine to unhealthy eyes [148]. The findings demonstrated a direct relationship between the average uptake of gold nanoparticles and the proportion of eyes that had healed, so validating the effectiveness of the method [148]. A novel composite delivery system based on carbon dots (CD C-HP ) and thermo-sensitive hydrogels was developed for the topical eye administration of diclofenac [149]. Hyaluronic acid and carboxymethyl chitosan were used in the synthesis of CD using a one-step hydrothermal technique. The resulting CD was then integrated in a thermo-sensitive in situ gel [149]. The CD C-HP -Gel composite provided enhanced pharmacokinetics and extended diclofenac release, demonstrating potential as a drug delivery system [149]. Furthermore, the fluorescence properties of CD allowed the tracking of diclofenac throughout intraocular tissues, demonstrating their efficiency as bioimaging agents [149]. 5. Conclusions The pursuit of non-invasive innovative therapies for posterior eye disorders is a priority and topical approaches are still the most appealing among patients. The idea of treating intraocular conditions with eye drops, hydrogels, or CL is as attractive as difficult. Indeed, following topical ophthalmic administration, therapeutic agents must face long and challenging paths (either through the corneal or conjunctival route) to reach posterior intraocular tissues and the retina. The well-defined anatomic structure of the eye includes several dynamic and static barriers that limit therapeutic delivery along the ocular compartments. As a result, drug bioavailability in the posterior portion of the eye is generally low. Nanomedicine is significantly contributing to overcoming these constraints, and the enhancement of topical treatments by the use of therapeutic loaded nanocarriers is a very promising strategy. The importance of the rational design of nanomedicines is one of the core messages of this review. Nanomedicines designed rationally based on their intended target, avoid unnecessary errors, and promote higher success rates. Therefore, we emphasize that nanomedicines should be carefully conceived considering the barriers they will encounter in each ophthalmic route. A compilation of experimental data from scientific literature and the physical–chemical characteristics of eye barriers is used to provide a collection of nanocarriers attributes tailored to effectively target posterior tissues. Both in the corneal and conjunctival route, it is determinant to: (i) use deformable soft-matter-based nanocarriers; (ii) use reduced size nanocarriers (≤300 nm); and (iii) balance the surface charge in accordance with to the barrier. The balance of the surface charge is particularly relevant because while cationic nanocarriers are promising in the initial stage, to interact and diffuse through the pre-corneal and corneal layers, further ahead they are not adequate and may be hindered in other structures like the vitreous humor. To fight back these dualities, a good option would be developing nanocarriers with mucoadhesive properties to increase interaction with the mucoaqueous layer at the eye surface. In these conditions, the development of neutrally or negatively charged nanocarriers would be advantageous, promoting their diffusion across the eye. Furthermore, besides deformability and size requirements, researchers can also use targeting strategies to enhance nanocarrier penetration into posterior tissues. The presence of several molecular transporter families and cell receptors at the conjunctiva, cornea, or RPE cells’ surface is an opportunity to mediate therapeutics distribution toward the target. In addition, permeation enhancers may be included within the nanocarrier M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 18 composition to increase ocular penetration. In addition, if therapeutic loaded nanocarriers are rapidly eliminated from the surface of the eye, it is feasible to include the formulations in other topical ophthalmic vehicles such as hydrogels or contact lenses. Overall, these strategies enable the balance between mucoadhesion and penetration, enhancing the therapeutic effect. Another interesting outlook of nanomedicine in the ophthalmic field is theranostics. Nanomedicines struggle to reach inner eye layers. Hence, it seems unquestionable that the possibility of real-time monitoring would provide critical information to healthcare professionals, either to clarify if the treatment is progressing appropriately or if the clinical situation needs to be reassessed. Theranostics can be a step in this direction, providing treatment and monitoring in the same device. CRediT authorship contribution statement Maria Jo˜ ao Faria: Conceptualization, Visualization, Writing – original draft, Writing – review and editing. Jos´ e M. Gonz´ alezM´ eijome: Writing – review and editing. M. Elisabete C.D. Real Oliveira: Supervision, Writing – review and editing. Gonzalo Carracedo: Supervision, Writing – review and editing. Marlene Lúcio: Conceptualization, Visualization, Supervision, Funding acquisition, Writing – review and editing. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data availability No data was used for the research described in the article. Acknowledgments This work was supported by the Portuguese Foundation for Science and Technology (FCT, UIDB/04650/2020, Portugal). Maria Jo˜ ao Faria acknowledges FCT I.P. for PhD grant (2020.06561.BD). The authors also thank Paula Pinto, PharmD, (PMA –. Pharmaceutical Medicine Academy) for providing medical writing and revision of the manuscript. References [1] GBD 2019 Blindness and Vision Impairment Collaborators, Vision Loss Expert Group of the Global Burden of Disease Study, Causes of blindness and vision impairment in 2020 and trends over 30 years, and prevalence of avoidable blindness in relation to VISION 2020: the Right to Sight: an analysis for the Global Burden of Disease Study, Lancet Glob. Heal. 9 (2021) (2019) 144–160, https://doi.org/10.1016/S2214-109X(20)30489-7. [2] C. Delcourt, J.F. Korobelnik, G.H.S. Buitendijk, P.J. Foster, C.J. Hammond, S. Piermarocchi, T. Peto, N. Jansonius, A. Mirshahi, R.E. Hogg, L. Bretillon, F. Topouzis, G. Deak, J. Grauslund, R. Broe, E.H. Souied, C. Creuzot-Garcher, J. Sahel, V. Daien, T. Lehtim¨ aki, H.W. Hense, E. Prokofyeva, K. Oexle, J.S. Rahi, P.M. Cumberland, S. Schmitz-Valckenberg, S. Fauser, G. Bertelsen, C. Hoyng, A. Bergen, R. Silva, S. Wolf, A. Lotery, U. Chakravarthy, A. Fletcher, C.C. W. Klaver, Ophthalmic epidemiology in Europe: the “European Eye Epidemiology” (E3) consortium, Eur. J. Epidemiol. 31 (2016) 197–210, https:// doi.org/10.1007/s10654-015-0098-2. [3] Y.C. Kim, B. Chiang, X. Wu, M.R. Prausnitz, Ocular delivery of macromolecules, J. Control. Release 190 (2014) 172–181, https://doi.org/10.1016/j. jconrel.2014.06.043. [4] A. Mandal, D. Pal, V. Agrahari, H.M. Trinh, M. Joseph, A.K. Mitra, Ocular delivery of proteins and peptides: challenges and novel formulation approaches, Adv. Drug Deliv. Rev. 126 (2018) 67–95, https://doi.org/10.1016/j. addr.2018.01.008. [5] GBD 2019 Blindness and Vision Impairment Collaborators, Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study, Lancet Glob. Heal. 9 (2021) (2019) 1–14, https://doi.org/10.1016/S2214-109X(20)30425-3. [6] S. Boddu, H. Gupta, S. Patel, Drug delivery to the back of the eye following topical administration: an update on research and patenting activity, Recent Pat. Drug Deliv. Formul. 8 (2014) 27–36, https://doi.org/10.2174/ 1872211308666140130093301. [7] A. Patel, K. Cholkar, V. Agrahari, A.K. Mitra, Ocular drug delivery systems: an overview, World J. Pharmacol. 2 (2013) 47–64, https://doi.org/10.5497/wjp.v2. i2.47. [8] Y. Weng, J. Liu, S. Jin, W. Guo, X. Liang, Z. Hu, Nanotechnology-based strategies for treatment of ocular disease, Acta Pharm. Sin. B 7 (2017) 281–291, https:// doi.org/10.1016/j.apsb.2016.09.001. [9] L. Battaglia, M. Gallarate, L. Serpe, F. Foglietta, E. Muntoni, A.P. Rodriguez, M.A. S. Aspiazu, Chapter 7 - Ocular delivery of solid lipid nanoparticles, in: A. Grumezescu (Ed.), Lipid Nanocarriers Drug Target, William Andrew Publishing, 2018, pp. 269–312, https://doi.org/10.1016/B978-0-12-8136874.00007-4. [10] J. Navarro-Partida, C.R. Castro-Castaneda, F.J.S. Cruz-Pavlovich, L.A. AcevesFranco, T.O. Guy, A. Santos, Lipid-based nanocarriers as topical drug delivery systems for intraocular diseases, Pharmaceutics 13 (2021) 1–25, https://doi.org/ 10.3390/pharmaceutics13050678. [11] P.W.J. Morrison, V.V. Khutoryanskiy, Advances in ophthalmic drug delivery, Ther. Deliv. 5 (2014) 1297–1315, https://doi.org/10.4155/tde.14.75. [12] V. Gote, S. Sikder, J. Sicotte, D. Pal, Ocular drug delivery: present innovations and future challenges, J. Pharmacol. Exp. Ther. 370 (2019) 602–624, https://doi.org/ 10.1124/jpet.119.256933. [13] A. Madni, M.A. Rahem, N. Tahir, M. Sarfraz, A. Jabar, M. Rehman, P.M. Kashif, S. F. Badshah, K.U. Khan, H.A. Santos, Non-invasive strategies for targeting the posterior segment of eye, Int. J. Pharm. 530 (2017) 326–345, https://doi.org/ 10.1016/j.ijpharm.2017.07.065. [14] R.R. Joseph, S.S. Venkatraman, Drug delivery to the eye: what benefits do nanocarriers offer? Nanomedicine 12 (2017) 683–702, https://doi.org/10.2217/ nnm-2016-0379. [15] A. Ameeduzzafar, J. Ali, M. Fazil, M. Qumbar, N. Khan, A. Ali, Colloidal drug delivery system: amplify the ocular delivery, Drug Deliv. 23 (2016) 700–726, https://doi.org/10.3109/10717544.2014.923065. [16] E.B. Souto, J. Dias-Ferreira, A. L´ opez-Machado, M. Ettcheto, A. Cano, A. C. Espuny, M. Espina, M.L. Garcia, E. S´ anchez-L´ opez, Advanced formulation approaches for ocular drug delivery: state-of-the-art and recent patents, Pharmaceutics 11 (2019) 1–29, https://doi.org/10.3390/ pharmaceutics11090460. [17] S. Kargozar, M. Mozafari, Nanotechnology and nanomedicine: start small, think big, Mater. Today:. Proc. 5 (2018) 15492–15500, https://doi.org/10.1016/j. matpr.2018.04.155. [18] S. Soares, J. Sousa, A. Pais, C. Vitorino, Nanomedicine: principles, properties, and regulatory issues, Front. Chem. 6 (2018) 1–15, https://doi.org/10.3389/ fchem.2018.00360. [19] Grand View Research Inc., Nanomedicine Market Size Worth, 2022, https ://www.grandviewresearch.com/press-release/global-nanomedicine-market. [20] D.A. Srinivasarao, G. Lohiya, D.S. Katti, Fundamentals, challenges, and nanomedicine-based solutions for ocular diseases, Wiley Interdiscip. Rev. Nanomed. NanoBiotechnol. 11 (2019) 1–26, https://doi.org/10.1002/ wnan.1548. [21] H. Han, S. Li, M. Xu, Y. Zhong, W. Fan, J. Xu, T. Zhou, J. Ji, J. Ye, K. Yao, Polymerand lipid-based nanocarriers for ocular drug delivery: current status and future perspectives, Adv. Drug Deliv. Rev. 196 (2023) 1–35, https://doi.org/ 10.1016/j.addr.2023.114770. [22] S. Gorantla, V.K. Rapalli, T. Waghule, P.P. Singh, S.K. Dubey, R.N. Saha, G. Singhvi, Nanocarriers for ocular drug delivery: current status and translational opportunity, RSC Adv. 10 (2020) 27835–27855, https://doi.org/10.1039/ d0ra04971a. [23] L. Bonilla, M. Espina, P. Severino, A. Cano, M. Ettcheto, A. Camins, M.L. García, E.B. Souto, E. S´ anchez-L´ opez, Lipid nanoparticles for the posterior eye segment, Pharmaceutics 14 (2022) 1–30, https://doi.org/10.3390/ pharmaceutics14010090. [24] K. Nayak, M. Misra, A review on recent drug delivery systems for posterior segment of eye, Biomed. Pharmacother. 107 (2018) 1564–1582, https://doi.org/ 10.1016/j.biopha.2018.08.138. [25] H.F. Edelhauser, C.L. Rowe-Rendleman, M.R. Robinson, D.G. Dawson, G. J. Chader, H.E. Grossniklaus, K.D. Rittenhouse, C.G. Wilson, D.A. Weber, B. D. Kuppermann, K.G. Csaky, T.W. Olsen, U.B. Kompella, V.M. Holers, G. S. Hageman, B.C. Gilger, P.A. Campochiaro, S.M. Whitcup, W.T. Wong, Ophthalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications, Invest. Ophthalmol. Vis. Sci. 51 (2010) 5403–5420, https://doi.org/10.1167/iovs.10-5392. [26] E.M. del Amo, A.K. Rimpel¨ a, E. Heikkinen, O.K. Kari, E. Ramsay, T. Lajunen, M. Schmitt, L. Pelkonen, M. Bhattacharya, D. Richardson, A. Subrizi, T. Turunen, M. Reinisalo, J. Itkonen, E. Toropainen, M. Casteleijn, H. Kidron, M. Antopolsky, K.S. Vellonen, M. Ruponen, A. Urtti, Pharmacokinetic aspects of retinal drug delivery, Prog. Retin. Eye Res. 57 (2017) 134–185, https://doi.org/10.1016/j. preteyeres.2016.12.001. [27] R. Varela-Fern´ andez, V. Díaz-Tom´ e, A. Luaces-Rodríguez, A. Conde-Penedo, X. García-Otero, A. Luzardo-´ alvarez, A. Fern´ andez-Ferreiro, F.J. Otero-Espinar, Drug delivery to the posterior segment of the eye: biopharmaceutic and pharmacokinetic considerations, Pharmaceutics 12 (2020) 1–39, https://doi.org/ 10.3390/pharmaceutics12030269. [28] J.J. Kang-Mieler, C.R. Osswald, W.F. Mieler, Advances in ocular drug delivery: emphasis on the posterior segment, Expert Opin. Drug Deliv. 11 (2014) 1647–1660, https://doi.org/10.1517/17425247.2014.935338. M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 19 [29] M. L¨ oscher, C. Seiz, J. Hurst, S. Schnichels, Topical drug delivery to the posterior segment of the eye, Pharmaceutics 14 (2022) 1–21, https://doi.org/10.3390/ pharmaceutics14010134. [30] Y. Wang, X. Xu, Y. Gu, Y. Cheng, F. Cao, Recent advance of nanoparticle-based topical drug delivery to the posterior segment of the eye, Expert Opin. Drug Deliv. 15 (2018) 687–701, https://doi.org/10.1080/17425247.2018.1496080. [31] S. Mohapatra, S. Ranjan, N. Dasgupta, R. Mishra, S. Thomas (Eds.), Nanocarriers for Drug Delivery, first ed., Elsevier, 2018. Doi: 10.1016/C2017-0-00199-4. [32] N. Mehra, S. Srivastava, J. Madan, P. Singh (Eds.), Multifunctional Nanocarriers, first ed., Elsevier, 2022. doi: 10.1016/C2020-0-02236-X. [33] K.G. Csaky, P.U. Dugel, A.J. Pierce, M.A. Fries, D.S. Kelly, R.P. Danis, J. I. Wurzelmann, C. Xu, M. Hossain, Clinical evaluation of Pazopanib eye drops versus Ranibizumab intravitreal injections in subjects with neovascular agerelated macular degeneration, Ophthalmology 122 (2015) 579–588, https://doi. org/10.1016/j.ophtha.2014.09.036. [34] Y. Yafai, X. Mei, M. Niemeyer, A. Nishiwaki, J. Lange, P. Wiedemann, A.G. King, T. Yasukawa, W. Eichler, Anti-angiogenic effects of the receptor tyrosine kinase inhibitor, pazopanib, on choroidal neovascularization in rats, Eur. J. Pharmacol. 666 (2011) 12–18, https://doi.org/10.1016/j.ejphar.2011.05.016. [35] M. V´ ezina, Chapter 1 - Comparative ocular anatomy in commonly used laboratory animals, in: A.B. Weir, M. Collins (Eds.), Assess. Ocul. Toxicol. Lab. Anim., Humana Totowan, NJ, 2012, pp. 1–21. doi: 10.1007/978-1-62703-164-6. [36] J.C. Altamirano-Vallejo, J. Navarro-Partida, A. Gonzalez-De La Rosa, J.H. Hsiao, J.S. Olguín-Gutierrez, A.C. Gonzalez-Villegas, B.C. Keller, L. Bouzo-Lopez, A. Santos, Characterization and pharmacokinetics of triamcinolone acetonideloaded liposomes topical formulations for vitreoretinal drug delivery, J. Ocul. Pharmacol. Ther. 34 (2018) 416–425, https://doi.org/10.1089/jop.2017.0099. [37] J. Li, T. Cheng, Q. Tian, Y. Cheng, L. Zhao, X. Zhang, Y. Qu, A more efficient ocular delivery system of triamcinolone acetonide as eye drop to the posterior segment of the eye, Drug Deliv. 26 (2019) 188–198, https://doi.org/10.1080/ 10717544.2019.1571122. [38] M. Khalil, U. Hashmi, R. Riaz, S. Rukh Abbas, Chitosan coated liposomes (CCL) containing triamcinolone acetonide for sustained delivery: a potential topical treatment for posterior segment diseases, Int. J. Biol. Macromol. 143 (2020) 483–491, https://doi.org/10.1016/j.ijbiomac.2019.10.256. [39] H. Shimazaki, K. Hironaka, T. Fujisawa, K. Tsuruma, Y. Tozuka, M. Shimazawa, H. Takeuchi, H. Hara, Edaravone-loaded liposome eyedrops protect against lightinduced retinal damage in mice, Invest. Ophthalmol. Vis. Sci. 52 (2011) 7289–7297, https://doi.org/10.1167/iovs.11-7983. [40] Y. Inokuchi, K. Hironaka, T. Fujisawa, Y. Tozuka, K. Tsuruma, M. Shimazawa, H. Takeuchi, H. Hara, Physicochemical properties affecting retinal drug/ coumarin-6 delivery from nanocarrier systems via eyedrop administration, Invest. Ophthalmol. Vis. Sci. 51 (2010) 3162–3170, https://doi.org/10.1167/iovs.094697. [41] H. Sasaki, K. Karasawa, K. Hironaka, K. Tahara, Y. Tozuka, H. Takeuchi, Retinal drug delivery using eyedrop preparations of poly-l-lysine-modified liposomes, Eur. J. Pharm. Biopharm. 83 (2013) 364–369, https://doi.org/10.1016/j. ejpb.2012.10.014. [42] T. Matsuo, I. Masuda, T. Yasuda, N. Matsuo, Gene transfer to the retina of rat by liposome eye drops, Biochem. Biophys. Res. Commun. 219 (1996) 947–950, https://doi.org/10.1006/bbrc.1996.0326. [43] T. Fujisawa, H. Miyai, K. Hironaka, T. Tsukamoto, K. Tahara, Y. Tozuka, M. Ito, H. Takeuchi, Liposomal diclofenac eye drop formulations targeting the retina: formulation stability improvement using surface modification of liposomes, Int. J. Pharm. 436 (2012) 564–567, https://doi.org/10.1016/j.ijpharm.2012.07.024. [44] B.M. Davis, E.M. Normando, L. Guo, L.A. Turner, S. Nizari, P. O’Shea, S.E. Moss, S. Somavarapu, M.F. Cordeiro, Topical delivery of avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes, Small 10 (2014) 1575–1584, https://doi.org/10.1002/smll.201303433. [45] C.B.M. Platania, V. Fisichella, A. Fidilio, F. Geraci, F. Lazzara, G.M. Leggio, S. Salomone, F. Drago, R. Pignatello, F. Caraci, C. Bucolo, Topical ocular delivery of TGF-β1 to the back of the eye: implications in age-related neurodegenerative diseases, Int. J. Mol. Sci. 18 (2017), https://doi.org/10.3390/ijms18102076. [46] P. Chetoni, S. Burgalassi, D. Monti, S. Tampucci, V. Tullio, A.M. Cuffini, E. Muntoni, R. Spagnolo, G.P. Zara, R. Cavalli, Solid lipid nanoparticles as promising tool for intraocular tobramycin delivery: pharmacokinetic studies on rabbits, Eur. J. Pharm. Biopharm. 109 (2016) 214–223, https://doi.org/10.1016/ j.ejpb.2016.10.006. [47] S. Kakkar, S.M. Karuppayil, J.S. Raut, F. Giansanti, L. Papucci, N. Schiavone, I. P. Kaur, Lipid-polyethylene glycol based nano-ocular formulation of ketoconazole, Int. J. Pharm. 495 (2015) 276–289, https://doi.org/10.1016/j. ijpharm.2015.08.088. [48] S.P. Balguri, G.R. Adelli, S. Majumdar, Topical ophthalmic lipid nanoparticle formulations (SLN, NLC) of indomethacin for delivery to the posterior segment ocular tissues, Eur. J. Pharm. Biopharm. 109 (2016) 224–235, https://doi.org/ 10.1016/j.ejpb.2016.10.015. [49] M. Yadav, N. Schiavone, A. Guzman-Aranguez, F. Giansanti, L. Papucci, M. J. Perez de Lara, M. Singh, I.P. Kaur, Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD), Drug Deliv. Transl. Res. 10 (2020) 919–944, https://doi.org/10.1007/ s13346-020-00777-6. [50] A. Tatke, N. Dudhipala, K.Y. Janga, S.P. Balguri, B. Avula, M.M. Jablonski, S. Majumdar, In situ gel of triamcinolone acetonide-loaded solid lipid nanoparticles for improved topical ocular delivery: tear kinetics and ocular disposition studies, Nanomaterials 9 (2019) 1–17, https://doi.org/10.3390/ nano9010033. [51] C. Puglia, D. Santonocito, C. Ostacolo, E.M. Sommella, P. Campiglia, C. Carbone, F. Drago, R. Pignatello, C. Bucolo, Ocular formulation based on palmitoylethanolamide-loaded nanostructured lipid carriers: technological and pharmacological profile, Nanomaterials 10 (2020) 1–11, https://doi.org/ 10.3390/nano10020287. [52] C. Puglia, P. Blasi, C. Ostacolo, E. Sommella, C. Bucolo, C.B.M. Platania, G. L. Romano, F. Geraci, F. Drago, D. Santonocito, B. Albertini, P. Campiglia, G. Puglisi, R. Pignatello, Innovative nanoparticles enhance Npalmitoylethanolamide intraocular delivery, Front. Pharmacol. 9 (2018) 1–7, https://doi.org/10.3389/fphar.2018.00285. [53] J. Araújo, S. Nikolic, M.A. Egea, E.B. Souto, M.L. Garcia, Nanostructured lipid carriers for triamcinolone acetonide delivery to the posterior segment of the eye, Colloids Surf. B Biointerfaces 88 (2011) 150–157, https://doi.org/10.1016/j. colsurfb.2011.06.025. [54] P. Lakhani, A. Patil, K.W. Wu, C. Sweeney, S. Tripathi, B. Avula, P. Taskar, S. Khan, S. Majumdar, Optimization, stabilization, and characterization of amphotericin B loaded nanostructured lipid carriers for ocular drug delivery, Int. J. Pharm. 572 (2019) 1–14, https://doi.org/10.1016/j.ijpharm.2019.118771. [55] R. Kapadia, K. Parikh, M. Jain, K. Sawant, Topical instillation of triamcinolone acetonide-loaded emulsomes for posterior ocular delivery: statistical optimization and in vitro-in vivo studies, Drug Deliv. Transl. Res. 11 (2021) 984–999, https:// doi.org/10.1007/s13346-020-00810-8. [56] Y. Ge, A. Zhang, R. Sun, J. Xu, T. Yin, H. He, J. Gou, J. Kong, Y. Zhang, X. Tang, Penetratin-modified lutein nanoemulsion in-situ gel for the treatment of agerelated macular degeneration, Expert Opin. Drug Deliv. 17 (2020) 603–619, https://doi.org/10.1080/17425247.2020.1735348. [57] L. Ying, K. Tahara, H. Takeuchi, Drug delivery to the ocular posterior segment using lipid emulsion via eye drop administration: effect of emulsion formulations and surface modification, Int. J. Pharm. 453 (2013) 329–335, https://doi.org/ 10.1016/j.ijpharm.2013.06.024. [58] X. Yang, L. Wang, L. Li, M. Han, S. Tang, T. Wang, J. Han, X. He, X. He, A. Wang, K. Sun, A novel dendrimer-based complex co-modified with cyclic RGD hexapeptide and penetratin for noninvasive targeting and penetration of the ocular posterior segment, Drug Deliv. 26 (2019) 989–1001, https://doi.org/ 10.1080/10717544.2019.1667455. [59] B. Yavuz, S.B. Pehlivan, I. Vural, N. Ünlü, In vitro/in vivo evaluation of dexamethasone - PAMAM dendrimer complexes for retinal drug delivery, J. Pharm. Sci. 104 (2015) 3814–3823, https://doi.org/10.1002/jps.24588. [60] C. Liu, K. Jiang, L. Tai, Y. Liu, G. Wei, W. Lu, W. Pan, Facile noninvasive retinal gene delivery enabled by penetratin, ACS Appl. Mater. Interfaces 8 (2016) 19256–19267, https://doi.org/10.1021/acsami.6b04551. [61] W.C. Huang, F. Cheng, C.C. Chen, P.H. Kuo, Y.J. Wang, S.C. Yin, C.M. Tu, M. H. Wu, W.Y. Wang, S.E. Chen, A novel eye drop formulation for potential treatment of neovascular age-related macular degeneration, Transl. Vis. Sci. Technol. 10 (2021) 1–11, https://doi.org/10.1167/tvst.10.14.23. [62] T. Loftsson, D. Hreinsd´ ottir, E. Stef´ ansson, Cyclodextrin microparticles for drug delivery to the posterior segment of the eye: aqueous dexamethasone eye drops, J. Pharm. Pharmacol. 59 (2010) 629–635, https://doi.org/10.1211/ jpp.59.5.0002. [63] M. Kallab, K. Schuetzenberger, N. Hommer, B.J. Sch¨ afer, D. Schmidl, H. Bergmeister, M. Zeitlinger, A. Tan, P. Jansook, T. Loftsson, E. Stefansson, G. Garh¨ ofer, Bio-distribution and pharmacokinetics of topically administered γ-cyclodextrin based eye drops in rabbits, Pharmaceuticals. 14 (2021) 1–10, https://doi.org/10.3390/ph14050480. [64] X. Zhao, I. Seah, K. Xue, W. Wong, Q. Shu Woon Tan, X. Ma, Q. Lin, J.Y.C. Lim, Z. Liu, B. Harshad Parikh, K.N. Mehta, J. Weijia Lai, B. Yang, K. Chi Tran, V. Amutha Barathi, K. Hao Cheong, W. Hunziker, X. Su, X. Jun Loh, Antiangiogenic nanomicelles for the topical delivery of aflibercept to treat retinal neovascular disease, Adv. Mater. 34 (2022) 1–14, https://doi.org/10.1002/ adma.202108360. [65] C. Di Tommaso, J.L. Bourges, F. Valamanesh, G. Trubitsyn, A. Torriglia, J. C. Jeanny, F. Behar-Cohen, R. Gurny, M. M¨ oller, Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies, Eur. J. Pharm. Biopharm. 81 (2012) 257–264, https://doi.org/10.1016/j.ejpb.2012.02.014. [66] S. Patel, C. Garapati, P. Chowdhury, H. Gupta, J. Nesamony, S. Nauli, S.H. S. Boddu, Development and evaluation of dexamethasone nanomicelles with potential for treating posterior Uveitis after topical application, J. Ocul. Pharmacol. Ther. 31 (2015) 215–227, https://doi.org/10.1089/jop.2014.0152. [67] K. Cholkar, S. Gunda, R. Earla, D. Pal, A.K. Mitra, Nanomicellar topical aqueous drop formulation of rapamycin for back-of-the-eye delivery, AAPS PharmSciTech 16 (2015) 610–622, https://doi.org/10.1208/s12249-014-0244-2. [68] R. Gonzalez-Pizarro, M. Silva-Abreu, A.C. Calpena, M.A. Egea, M. Espina, M. L. García, Development of fluorometholone-loaded PLGA nanoparticles for treatment of inflammatory disorders of anterior and posterior segments of the eye, Int. J. Pharm. 547 (2018) 338–346, https://doi.org/10.1016/j. ijpharm.2018.05.050. [69] K. Tahara, K. Karasawa, R. Onodera, H. Takeuchi, Feasibility of drug delivery to the eye’s posterior segment by topical instillation of PLGA nanoparticles, Asian J. Pharm. Sci. 12 (2017) 394–399, https://doi.org/10.1016/j.ajps.2017.03.002. [70] B. Silva, L.M. Gonçalves, B. S˜ ao Braz, E. Delgado, Topical ocular delivery of nanoparticles with epoetin beta in Wistar Hannover rats, Sci. Rep. 13 (2023) 1–12, https://doi.org/10.1038/s41598-023-28845-0. [71] G. Esteruelas, L. Halbaut, V. García-Torra, M. Espina, A. Cano, M. Ettcheto, A. Camins, E.B. Souto, M. Luisa García, E. S´ anchez-L´ opez, Development and optimization of Riluzole-loaded biodegradable nanoparticles incorporated in a M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 20 mucoadhesive in situ gel for the posterior eye segment, Int. J. Pharm. 612 (2022) 1–13, https://doi.org/10.1016/j.ijpharm.2021.121379. [72] S.E.S. Radwan, A. El-Kamel, E.I. Zaki, S. Burgalassi, E. Zucchetti, R.M. ElMoslemany, Hyaluronic-coated albumin nanoparticles for the non-invasive delivery of apatinib in diabetic retinopathy, Int. J. Nanomed. 16 (2021) 4481–4494, https://doi.org/10.2147/IJN.S316564. [73] A. Popov, Mucus-penetrating particles and the role of ocular mucus as a barrier to microand nanosuspensions, J. Ocul. Pharmacol. Ther. 36 (2020) 366–375, https://doi.org/10.1089/jop.2020.0022. [74] Y. Gu, C. Xu, Y. Wang, X. Zhou, L. Fang, F. Cao, Multifunctional nanocomposites based on liposomes and layered double hydroxides conjugated with glycylsarcosine for efficient topical drug delivery to the posterior segment of the eye, Mol. Pharm. 16 (2019) 2845–2857, https://doi.org/10.1021/acs. molpharmaceut.8b01136. [75] A. Laradji, B.B. Karakocak, A.V. Kolesnikov, V.J. Kefalov, N. Ravi, Hyaluronic acid-based gold nanoparticles for the topical delivery of therapeutics to the retina and the retinal pigment epithelium, Polymers (basel). 13 (2021) 1–10, https:// doi.org/10.3390/polym13193324. [76] S. Sripetch, T. Loftsson, Topical drug delivery to the posterior segment of the eye: thermodynamic considerations, Int. J. Pharm. 597 (2021) 1–8, https://doi.org/ 10.1016/j.ijpharm.2021.120332. [77] R.A. Cone, Barrier properties of mucus, Adv. Drug Deliv. Rev. 61 (2009) 75–85, https://doi.org/10.1016/j.addr.2008.09.008. [78] V. Agrahari, A. Mandal, V. Agrahari, H.M. Trinh, M. Joseph, A. Ray, H. Hadji, R. Mitra, D. Pal, A.K. Mitra, A comprehensive insight on ocular pharmacokinetics, Drug Deliv. Transl. Res. 6 (2016) 735–754, https://doi.org/10.1007/s13346-0160339-2. [79] L.M. Ensign, C. Schneider, J.S. Suk, R. Cone, J. Hanes, Mucus penetrating nanoparticles: biophysical tool and method of drug and gene delivery, Adv. Mater. 24 (2012) 3887–3894, https://doi.org/10.1002/adma.201201800. [80] J. Witten, T. Samad, K. Ribbeck, Selective permeability of mucus barriers, Curr. Opin. Biotechnol. 52 (2018) 124–133, https://doi.org/10.1016/j. copbio.2018.03.010. [81] J. Leal, H.D.C. Smyth, D. Ghosh, Physicochemical properties of mucus and their impact on transmucosal drug delivery, Int. J. Pharm. 532 (2017) 555–572, https://doi.org/10.1016/j.ijpharm.2017.09.018. [82] J. Cunha-Vaz, R. Bernardes, C. Lobo, Blood-retinal barrier, Eur. J. Ophthalmol. 21 (2011) 3–9, https://doi.org/10.5301/EJO.2010.6049. [83] T. A, S. PK, M. R, Role of blood retinal barrier in drug absorption, Pharm. Anal. Acta. 9 (2018) 1–5. doi: 10.4172/2153-2435.1000585. [84] J. Park, Y. Zhang, N. Vykhodtseva, J.D. Akula, N.J. McDannold, Targeted and reversible blood-retinal barrier disruption via focused ultrasound and microbubbles, PLoS One 7 (2012) 1–8, https://doi.org/10.1371/journal. pone.0042754. [85] B. Williamson, V. Pilla Reddy, Blood retinal barrier and ocular pharmacokinetics: considerations for the development of oncology drugs, Biopharm. Drug Dispos. 42 (2021) 128–136, https://doi.org/10.1002/bdd.2276. [86] L. Liu, X. Liu, Chapter 10 - Roles of drug transporters in blood-retinal barrier, in: G. Pan, X. Liu (Eds.), Drug Transp. Drug Dispos. Eff. Toxic., Springer Singapore, Singapore, 2019, pp. 467–504, https://doi.org/10.1007/978-981-13-7647-4. [87] H. Ragelle, A. Goncalves, S. Kustermann, D.A. Antonetti, A. Jayagopal, Organ-ona-chip technologies for advanced blood-retinal barrier models, J. Ocul. Pharmacol. Ther. 36 (2020) 30–41, https://doi.org/10.1089/jop.2019.0017. [88] K. Cholkar, S.R. Dasari, D. Pal, A.K. Mitra, Chapter 1 - Eye: anatomy, physiology and barriers to drug delivery, in: A.K. Mitra (Ed.), Ocul. Transp. Recept. Their Role Drug Deliv, first ed., Woodhead Publishing Limited, 2013, pp. 1–36, https:// doi.org/10.1533/9781908818317.1. [89] L. Gan, J. Wang, M. Jiang, H. Bartlett, D. Ouyang, F. Eperjesi, J. Liu, Y. Gan, Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers, Drug Discov. Today 18 (2013) 290–297, https://doi.org/10.1016/j. drudis.2012.10.005. [90] H.S. Dua, L.A. Faraj, D.G. Said, T. Gray, J. Lowe, Human corneal anatomy redefined: a novel pre-descemet’s layer (Dua’s Layer), Ophthalmology 120 (2013) 1778–1785, https://doi.org/10.1016/j.ophtha.2013.01.018. [91] R. Bisht, A. Mandal, J.K. Jaiswal, I.D. Rupenthal, Nanocarrier mediated retinal drug delivery: overcoming ocular barriers to treat posterior eye diseases, Wiley Interdiscip. Rev. Nanomed. NanoBiotechnology 10 (2018) 1–21, https://doi.org/ 10.1002/wnan.1473. [92] L.M. Magalh˜ aes, C. Nunes, M. Lúcio, M.A. Segundo, S. Reis, J.L.F.C. Lima, Highthroughput microplate assay for the determination of drug partition coefficients, Nat. Protoc. 5 (2010) 1823–1830, https://doi.org/10.1038/nprot.2010.137. [93] M. Ali, M.E. Byrne, Challenges and solutions in topical ocular drug-delivery systems, Expert. Rev. Clin. Pharmacol. 1 (2008) 145–161, https://doi.org/ 10.1586/17512433.1.1.145. [94] A. Subrizi, E.M. del Amo, V. Korzhikov-Vlakh, T. Tennikova, M. Ruponen, A. Urtti, Design principles of ocular drug delivery systems: importance of drug payload, release rate, and material properties, Drug Discov. Today 24 (2019) 1446–1457, https://doi.org/10.1016/j.drudis.2019.02.001. [95] J. Lee, R.M. Pelis, Drug transport by the blood-aqueous humor barrier of the eye, Drug Metab. Dispos. 44 (2016) 1675–1681, https://doi.org/10.1124/ dmd.116.069369. [96] J. Cunha-Vaz, The blood-ocular barriers, Surv. Ophthalmol. 23 (1979) 279–296, https://doi.org/10.1016/0039-6257(79)90158-9. [97] J. Mains, C.G. Wilson, The vitreous humor as a barrier to nanoparticle distribution, J. Ocul. Pharmacol. Ther. 29 (2013) 143–150, https://doi.org/ 10.1016/j.jconrel.2020.10.028. [98] N.K. Tram, C.J. Maxwell, K.E. Swindle-Reilly, Macroand microscale properties of the vitreous humor to inform substitute design and intravitreal biotransport, Curr. Eye Res. 46 (2021) 429–444, https://doi.org/10.1080/ 02713683.2020.1826977. [99] N.K. Tram, K.E. Swindle-Reilly, Rheological properties and age-related changes of the human vitreous humor, Front. Bioeng. Biotechnol. 6 (2018) 1–12, https://doi. org/10.3389/fbioe.2018.00199. [100] K. Peynshaert, J. Devoldere, A.K. Minnaert, S.C. De Smedt, K. Remaut, Morphology and composition of the inner limiting membrane: species-specific variations and relevance toward drug delivery research, Curr. Eye Res. 44 (2019) 465–475, https://doi.org/10.1080/02713683.2019.1565890. [101] M.J. Faria, R. Machado, A. Ribeiro, H. Gonçalves, M.E.C.D. Real Oliveira, T. Viseu, M. Lúcio, Rational development of liposomal hydrogels : a strategy for topical vaginal antiretroviral drug delivery in the context of HIV prevention, Pharmaceutics 11 (2019) 1–27, https://doi.org/10.3390/ pharmaceutics11090485. [102] A. Prabakaran, A. Alexander, Biophysical analysis on molecular interactions between chitosan-coated sinapic acid loaded liposomes and mucin, Biochim. Biophys. Acta - Gen. Subj. 2024 (1868) 1–9, https://doi.org/10.1016/j. bbagen.2023.130517. [103] Z. N´ emeth, I. Cs´ oka, R. Semnani Jazani, B. Sipos, H. Haspel, G. Kozma, Z. K´ onya, D.G. Dob´ o, Quality by design-driven zeta potential optimisation study of liposomes with charge imparting membrane additives, Pharmaceutics 14 (2022) 1–25, https://doi.org/10.3390/pharmaceutics14091798. [104] M. Lúcio, N. Giannino, S. Barreira, J. Catita, H. Gonçalves, A. Ribeiro, E. Fernandes, I. Carvalho, H. Pinho, F. Cerqueira, M. Biondi, C.M. Lopes, Nanostructured lipid carriers enriched hydrogels for skin topical administration of quercetin and omega-3 fatty acid, Pharmaceutics 15 (2023) 1–22, https://doi. org/10.3390/pharmaceutics15082078. [105] J. das Neves, M.F. Bahia, M.M. Amiji, B. Sarmento, Mucoadhesive nanomedicines: characterization and modulation of mucoadhesion at the nanoscale, Expert Opin. Drug Deliv. 8 (2011) 1085–1104, https://doi.org/10.1517/ 17425247.2011.586334.34. [106] S.A. Mustfa, E. Maurizi, J. McGrath, C. Chiappini, Nanomedicine approaches to negotiate local biobarriers for topical drug delivery, Adv. Ther. 4 (2021) 1–27, https://doi.org/10.1002/adtp.202000160. [107] R. Suri, S. Beg, K. Kohli, Target strategies for drug delivery bypassing ocular barriers, J. Drug Deliv. Sci. Technol. 55 (2020) 1–17, https://doi.org/10.1016/j. jddst.2019.101389. [108] A. Mihai Grumezescu (Ed.), Organic Materials as Smart Nanocarriers for Drug Delivery, first ed., William Andrew Publishing, 2018. doi: 10.1016/C2016-004124-4. [109] M.G. Qaddoumi, H. Ueda, J. Yang, J. Davda, V. Labhasetwar, V.H.L. Lee, The characteristics and mechanisms of uptake of PLGA nanoparticles in rabbit conjunctival epithelial cell layers, Pharm. Res. 21 (2004) 641–648, https://doi. org/10.1023/B:PHAM.0000022411.47059.76. [110] A.C. Amrite, U.B. Kompella, Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration, J. Pharm. Pharmacol. 57 (2010) 1555–1563, https://doi.org/10.1211/jpp.57.12.0005. [111] A.C. Amrite, H.F. Edelhauser, S.R. Singh, U.B. Kompella, Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration, Mol. Vis. 14 (2008) 150–160. [112] A. Thareja, H. Hughes, C. Alvarez-lorenzo, J.J. Hakkarainen, Z. Ahmed, Penetration enhancers for topical drug delivery to the ocular posterior segment — A systematic review, Pharmaceutics 13 (2021) 1–17, https://doi.org/10.3390/ pharmaceutics13020276. [113] R.V. Moiseev, P.W.J. Morrison, F. Steele, V.V. Khutoryanskiy, Penetration enhancers in ocular drug delivery, Pharmaceutics 11 (2019) 1–33, https://doi. org/10.3390/pharmaceutics11070321. [114] S.P. Vyas, R. Paliwal, S.R. Paliwal, Chapter 5 - Ocular delivery of peptides and proteins, in: C. Van Der Walle (Ed.), Pept. Protein Deliv., Elsevier, 2011, pp. 87–103. doi: 10.1016/B978-0-12-384935-9.10005-7. [115] P.K. Karla, R. Earla, S.H. Boddu, T.P. Johnston, D. Pal, A. Mitra, Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells, Curr. Eye Res. 34 (2009) 1–9, https://doi.org/10.1080/ 02713680802518251. [116] F.A. Maulvi, T.G. Soni, D.O. Shah, A review on therapeutic contact lenses for ocular drug delivery, Drug Deliv. 23 (2016) 3017–3026, https://doi.org/ 10.3109/10717544.2016.1138342. [117] Q. Xu, N.J. Boylan, J.S. Suk, Y.Y. Wang, E.A. Nance, J.C. Yang, P.J. McDonnell, R. A. Cone, E.J. Duh, J. Hanes, Nanoparticle diffusion in, and microrheology of, the bovine vitreous ex vivo, J. Control. Release 167 (2013) 76–84, https://doi.org/ 10.1016/j.jconrel.2013.01.018. [118] B.T. K¨ asdorf, F. Arends, O. Lieleg, Diffusion regulation in the vitreous humor, Biophys. J . 109 (2015) 2171–2181, https://doi.org/10.1016/j.bpj.2015.10.002. [119] K. Peynshaert, J. Devoldere, S.C. De Smedt, K. Remaut, In vitro and ex vivo models to study drug delivery barriers in the posterior segment of the eye, Adv. Drug Deliv. Rev. 126 (2018) 44–57, https://doi.org/10.1016/j.addr.2017.09.007. [120] W. Halfter, J. Sebag, E.T. Cunningham, Chapter II.3: Vitreoretinal interface and inner limiting membrane, in: J. Sebag (Ed.), Vitr. Heal. Dis., Springer New York, NY, New York, 2014, pp. 165–191. [121] H. Koo, H. Moon, H. Han, J.H. Na, M.S. Huh, J.H. Park, S.J. Woo, K.H. Park, I. Chan Kwon, K. Kim, H. Kim, The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection, Biomaterials 33 (2012) 3485–3493, https://doi.org/10.1016/j. biomaterials.2012.01.030. M.J. Faria et al. Advanced Drug Delivery Reviews 210 (2024) 115321 21 [122] K. Peynshaert, J. Devoldere, V. Forster, S. Picaud, C. Vanhove, S.C. De Smedt, K. Remaut, Toward smart design of retinal drug carriers: a novel bovine retinal explant model to study the barrier role of the vitreoretinal interface, Drug Deliv. 24 (2017) 1384–1394, https://doi.org/10.1080/10717544.2017.1375578. [123] R. Agarwal, I. Iezhitsa, P. Agarwal, N.A. Abdul Nasir, N. Razali, R. Alyautdin, N. M. Ismail, Liposomes in topical ophthalmic drug delivery: an update, Drug Deliv. 23 (2016) 1075–1091, https://doi.org/10.3109/10717544.2014.943336. [124] P. Agarwal, J.P. Craig, I.D. Rupenthal, Formulation considerations for the management of dry eye disease, Pharmaceutics 13 (2021) 1–19, https://doi.org/ 10.3390/pharmaceutics13020207. [125] L. Battaglia, L. Serpe, F. Foglietta, E. Muntoni, M. Gallarate, A. Del Pozo Rodriguez, M.A. Solinis, Application of lipid nanoparticles to ocular drug delivery, Expert Opin. Drug Deliv. 13 (2016) 1743–1757, https://doi.org/ 10.1080/17425247.2016.1201059. [126] D.C.T. Nguyen, J. Dowling, R. Ryan, P. McLoughlin, L. Fitzhenry, Pharmaceuticalloaded contact lenses as an ocular drug delivery system: a review of critical lens characterization methodologies with reference to ISO standards, Contact Lens Anterior Eye 44 (2021) 1–17, https://doi.org/10.1016/j.clae.2021.101487. [127] S. Dey, A.K. Mitra, Transporters and receptors in ocular drug delivery: opportunities and challenges, Expert Opin. Drug Deliv. 2 (2005) 201–204, https://doi.org/10.1517/17425247.2.2.201. [128] P. Chen, H. Chen, X. Zang, M. Chen, H. Jiang, S. Han, X. Wu, Expression of efflux transporters in human ocular tissues, Drug Metab. Dispos. 41 (2013) 1934–1948, https://doi.org/10.1124/dmd.113.052704. [129] S.H. Kim, R.J. Lutz, N.S. Wang, M.R. Robinson, Transport barriers in transscleral drug delivery for retinal diseases, Ophthalmic Res. 39 (2007) 244–254, https:// doi.org/10.1159/000108117. [130] L. Pitk¨ anen, V.P. Ranta, H. Moilanen, A. Urtti, Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity, Invest. Ophthalmol. Vis. Sci. 46 (2005) 641–646, https://doi.org/10.1167/iovs.04-1051. [131] A.K. Rimpel¨ a, M. Reinisalo, L. Hellinen, E. Grazhdankin, H. Kidron, A. Urtti, E. M. del Amo, Implications of melanin binding in ocular drug delivery, Adv. Drug Deliv. Rev. 126 (2018) 23–43, https://doi.org/10.1016/j.addr.2017.12.008. [132] P. Franco, I. De Marco, Soft contact lenses as drug delivery systems: a review, Polymers (basel). 13 (2021) 1–22, https://doi.org/10.3390/molecules26185577. [133] C.R. Lynch, P.P.D. Kondiah, Y.E. Choonara, L.C. du Toit, N. Ally, V. Pillay, Hydrogel biomaterials for application in ocular drug delivery, Front. Bioeng. Biotechnol. 8 (2020) 1–18, https://doi.org/10.3389/fbioe.2020.00228. [134] R.C. Cooper, H. Yang, Hydrogel-based ocular drug delivery systems: emerging fabrication strategies, applications, and bench-to-bedside manufacturing considerations, J. Control. Release 306 (2019) 29–39, https://doi.org/10.1016/j. jconrel.2019.05.034. [135] R. Cassano, M.L. Di Gioia, S. Trombino, Gel-based materials for ophthalmic drug delivery, Gels 7 (2021) 1–15, https://doi.org/10.3390/gels7030130. [136] D. Nunes, S. Andrade, M.J. Ramalho, J.A. Loureiro, M.C. Pereira, Polymeric nanoparticles-loaded hydrogels for biomedical applications: a systematic review on in vivo findings, Polymers (basel). 14 (2022) 1–28, https://doi.org/10.3390/ polym14051010. [137] S. Gholizadeh, Z. Wang, X. Chen, R. Dana, N. Annabi, Advanced nanodelivery platforms for topical ophthalmic drug delivery, Drug Discov. Today 26 (2021) 1437–1449, https://doi.org/10.1016/j.drudis.2021.02.027. [138] I. Rykowska, I. Nowak, R. Nowak, Soft contact lenses as drug delivery systems: a review, Molecules 26 (2021) 1–31, https://doi.org/10.3390/molecules26185577. [139] A.E. Ross, L.C. Bengani, R. Tulsan, D.E. Maidana, B. Salvador-Culla, H. Kobashi, P. E. Kolovou, H. Zhai, K. Taghizadeh, L. Kuang, M. Mehta, D.G. Vavvas, D. S. Kohane, J.B. Ciolino, Topical sustained drug delivery to the retina with a drugeluting contact lens, Biomaterials 217 (2019) 1–13, https://doi.org/10.1016/j. biomaterials.2019.119285. [140] S.S. Kelkar, T.M. Reineke, Theranostics: combining imaging and therapy, Bioconjug. Chem. 22 (2011) 1879–1903, https://doi.org/10.1021/bc200151q. [141] D. Singh, F. Dilnawaz, S.K. Sahoo, Challenges of moving theranostic nanomedicine into the clinic, Nanomedicine 15 (2020) 111–114, https://doi.org/ 10.2217/nnm-2019-0401. [142] B. Theek, L.Y. Rizzo, J. Ehling, F. Kiessling, T. Lammers, The theranostic path to personalized nanomedicine, Clin. Transl. Imaging. 2 (2014) 67–76, https://doi. org/10.1007/s40336-014-0051-5. [143] C. Zavaleta, D. Ho, E. Ji Chung, Theranostic nanoparticles for tracking and monitoring disease state, SLAS Technol. 23 (2018) 281–293, https://doi.org/ 10.1177/2472630317738699. [144] D.H. Keum, S.K. Kim, J. Koo, G.H. Lee, C. Jeon, J.W. Mok, B.H. Mun, K.J. Lee, E. Kamrani, C.K. Joo, S. Shin, J.Y. Sim, D. Myung, S.H. Yun, Z. Bao, S.K. Hahn, Wireless smart contact lens for diabetic diagnosis and therapy, Sci. Adv. 6 (2020) 1–13, https://doi.org/10.1126/sciadv.aba3252. [145] T.Y. Kim, J.W. Mok, S.H. Hong, S.H. Jeong, H. Choi, S. Shin, C.K. Joo, S.K. Hahn, Wireless theranostic smart contact lens for monitoring and control of intraocular pressure in glaucoma, Nat. Commun. 13 (2022) 1–12, https://doi.org/10.1038/ s41467-022-34597-8. [146] W.C. Mak, K.Y. Cheung, J. Orban, C.J. Lee, A.P.F. Turner, M. Griffith, Surfaceengineered contact lens as an advanced theranostic platform for modulation and detection of viral infection, ACS Appl. Mater. Interfaces 7 (2015) 25487–25494, https://doi.org/10.1021/acsami.5b08644. [147] M. Tang, X. Ji, H. Xu, L. Zhang, A. Jiang, B. Song, Y. Su, Y. He, Photostable and biocompatible fluorescent silicon nanoparticles-based theranostic probes for simultaneous imaging and treatment of ocular neovascularization, Anal. Chem. 90 (2018) 8188–8195, https://doi.org/10.1021/acs.analchem.8b01580. [148] H.F. Salem, S.M. Ahmed, M.M. Omar, Liposomal flucytosine capped with gold nanoparticle formulations for improved ocular delivery, Drug Des. Devel. Ther. 10 (2016) 277–295, https://doi.org/10.2147/DDDT.S91730. [149] L. Wang, H. Pan, D. Gu, H. Sun, K. Chen, G. Tan, W. Pan, A novel carbon dots/ thermo-sensitive in situ gel for a composite ocular drug delivery system: characterization, ex-vivo imaging and in vivo evaluation, Int. J. Mol. Sci. 22 (2021) 1–16, https://doi.org/10.3390/ijms22189934. M.J. Faria et al.