The landscape of ophthalmic care has experienced transformative changes over the past few decades, notably due to technological advancements and innovative materials science. Among the burgeoning frontiers in this interdisciplinary field is the application of nanoporous materials, characterized by their unique physicochemical properties and potential for sophisticated functionality [1].

Nanoporous materials are distinguished by their high surface area, tunable porosity, and capacity for functional modifications, which make them apt for potentially enhancing the bioavailability and controlled release of therapeutic agents [2,3]. Furthermore, these materials offer some advantages in potentially improving the performance and user experience in ocular devices like contact and intraocular lenses [4,5]. The prospects of these applications, however, are not without challenges; issues related to biocompatibility, manufacturing scalability, and long-term stability warrant thorough investigation [6].

2. Understanding Nanoporous Materials

2.1. Definition and Characteristics

2.2. The Potential as Ophthalmic Drug Carriers

Much attention in the past has been centered around nanoparticle synthesis and design. While still limited, in recent years, researchers have centered their studies around the applications of nanoporous materials as DDS for the treatment of various ocular diseases, such as glaucoma, cataracts, or dry eye [34,35,36]. Common porous carriers, such as nanoporous hydrogel, mesoporous silica, nanoporous silica, and nanoporous nanofibers, have been developed recently and used for the treatment of anterior and posterior segment diseases (Table 1).

Indication	Drug	DDS	Advantages and Considerations	Administration Route	Stage	Reference
Corneal abrasion	Epigallocatechin gallate (EGCG); 8-1,3-glucan; and SB431542	Nanoporous hydrogels	Controlled and sequential release of multiple drugs tailored to address different stages of corneal tissue repair.	Topical	Preclinical—in vitro	[37]
Glaucoma	Nitric oxide (NO)	Mesoporous silica nanoparticles	Increased tissue permeability; tissue targeting; and drug penetration. Sustainable and stable delivery of NO to tissue site.	Topical	Preclinical—in vitro and in vivo	[34]
Ocular neovascularisation	Bevacizumab	Mesoporous silica nanoparticles	Effective preservation of bevacizumab concentration, without causing toxicity to tissues.	Injection (subconjunctival)	Preclinical—in vitro and in vivo	[38]
Posterior uveitis	Tacrolimus	Mesoporous silica nanoparticles	DDS achieved up to 7% TAC loading, without any damage to the retinal tissue or optic nerve tissue.	Injection (intravitreal)	Preclinical—in vitro and in vivo	[39]
Postoperative pterygium recurrence	Mitomycin C (MMC)	Mesoporous silica nanoparticles	Targeting and delivery of MMC was effective and the nanoparticles exhibited less toxicity compared to normal fibroblasts.	Injection (subconjunctival)	Preclinical—in vitro and in vivo	[40]
Posterior uveitis	Methotrexate (MTX)	Nanoporous polymers	DDS did not show any toxicity, immune or foreign body responses following implantation.	Implantation	Preclinical—in vitro and in vivo	[41]
Conjunctivitis	Gentamicin and dexamethasone	Nanoporous Naofibers	Prolonged resistance time, increased tear fluid viscosity and contact time.	Topical	Preclinical—in vitro and ex vivo	[42]
Subconjunctival fibrosis	Celastrol	Nanoporous nanofibers	DDS prevented burse release of celastrol and was still able to preserve the important PI3K/Akt/mTOR pathway-inhibiting effect of celastrol.	Implantation	Preclinical—in vitro and in vivo	[43]

Hydrogels consist of three-dimension networks of polymer chains that can absorb a large amount of water, at least 10% of their total weight or volume, while maintaining their structural integrity [44]. Their flexibility is similar to that of natural human tissue, and they can be chemically modified based on the characteristics of their environments, such as temperature, pH, solvent composition, and electrical field presence [45,46]. Due to their high porosity, which can be adjusted through crosslinking or by modifying their affinity for the aqueous environment, hydrogels serve as excellent DDS that are highly permeable to different types of molecules and drugs [47]. For instance, although the most common treatment approach for cornea abrasion (CA) includes antibiotic drops and ointments, they often do not work as anticipated or as effectively, due to the lack of patient compliance [48]. Luo et al. (2022) [37] therefore developed a therapeutic hydrogel sheet (THS) composed of a functional hydrogel, consisting of a poly(hydroxyethyl methacrylate), positively-charged chitosan, and zinc oxide nanoparticles, and a ternary drug-carrier system, consisting of dipalmitoylphosphatidylcholine liposome (DPPC), nanoparticles with epigallocatechin gallate (EGCG), and hyaluronic acid nanoparticles to improve treatment for CA. After tailoring the degradability, the researcher found that the THS could be specifically tailored for multistage drug release. Their results showed that the THS decreased the inflammatory response at the beginning stage, promoted wound healing at the middle stage, and prevented scar formation at the final stage that follows CA. They validated this model in rabbits and showed that the percent recovery was 90%, which represents more than an eight-fold increase compared to that of conventional eye drops. Although recent literature remains limited, the application of nanoporous hydrogels holds considerable potential as a major component in ocular DDS, offering avenues for improving treatment precision and clinical outcomes. To build off the current study, research efforts should be centered around investigating if the DDS developed by Luo et al. (2022) is compatible with other ocular drugs and could be used for treating more complex ocular diseases.

Mesoporous silica and nanoporous silica are inorganic nanoporous materials, synthesized from sodium silicates or silica tetraethyl orthosilicate with a surfactant micelle [49]. They have pore sizes ranging from 2 nm to 50 nm and <2 nm in diameter, respectively, which can be tuned based on various environmental influences, such as the morphology of surfactants, temperature, and pH conditions [50]. Their high surface area, uniform yet tunable pore size, biocompatibility, pore volume, and convenient manufacturing process present them as suitable carriers for ocular drug delivery [51,52,53].

In light of these developments, recent studies have investigated innovative drug delivery systems such as hollow mesoporous organosilica (HOS) nanocapsules for co-delivering NO donor drugs to the eye as potential glaucoma treatments. Glaucoma is a complex, multifactorial ocular disease often characterized by the progressive degeneration of the optic nerve. Although various risk factors have been implicated, intraocular pressure (IOP) remains the most important modifiable risk factor. Traditional medical and surgical interventions predominantly focus on lowering IOP to halt or slow the disease’s progression. As our understanding of glaucoma deepens, emerging research is exploring the role of physiological mediators like nitric oxide (NO) in disease management. NO is not only involved in reducing IOP but may also have a role in improving the perfusion of the optic nerve head, offering a multi-faceted approach to treatment. Latanoprostene bunod 0.024%, for instance, is a therapeutic agent that has demonstrated promise in clinical trials in this regard [54]. In one study, Fan et al. (2021) [34] investigated the use of hollow mesoporous organosilica (HOS) nanocapsules as a DDS for co-delivering nitrogen oxide (NO) donor drugs hydrophobic JS-K (diazeniumdiolates) (J_R) and hydrophilic L-Arginine (L_o) to the eye as a potential treatment for glaucoma. They loaded J_R and L_o into the internal cavity and mesoporous shell and found that the synthesized silica showed high stability and biocompatibility during degradation. After testing the HOS’s ability to deliver NO donors (J_R/L_O) to the target tissue on a Cav1 knockout (KO) mice, which was observed to have higher intraocular pressure (IOP) compared to a Cav1 mice, they found that the HOS showed greater tissue permeability and was able to directly transport the drug to the tissue of interest. Additionally, Fan and collaborators investigated the long-term side effects of HOS-based NO nanotherapeutics as current sustained NO donor treatments tend to release NO in excess, which can lead to cell damage. After treating the Cav1 KO mice with the HOS-J_RL_O, every 48 h, they found that across 10 days, the IOP still decreased, showing that the HOS was able to release the NO in a sustained and stable fashion, thus preventing tissue damage, while still decreasing IOP [55]. They found similar results when validating the generality of the HOS-based NO nanotherapeutics on another ocular hypertension mice model. Subsequent analyses showed that the HOS-based NO nanotherapeutics model regulated the IOP reduction through different methods, such as decreasing humor outflow resistance. It would be critical to know the exact factors in different models that affect IOP reduction. Future research should focus on validating this model using other medications and in other disease mice models.

In another study, Sun et al. (2019) [38] looked at the potential of using mesoporous silica nanoparticles as a nanodrug delivery system of bevacizumab to improve antiangiogenic therapy for retinal and choroidal neovascularisation. This pathological condition is associated with ophthalmic diseases such as ischemic retinal vein occlusion (RVO), proliferative diabetic retinopathy (PDR), and wet age-related macular degeneration (wet-ARMD). These conditions can lead to severe consequences like intravitreal hemorrhage, retinal detachment, and neovascular glaucoma, all of which pose acute risks of blindness. Bevacizumab, one among several anti-VEGF treatments that include agents such as aflibercept, ranibizumab, and faricimab, possesses antiangiogenic properties. These agents have collectively demonstrated efficacy in reducing neovascularization and inducing its regression. Presently, the standard approach for administering treatments like bevacizumab is through intravitreal injections. However, this method necessitates frequent visits to ophthalmologists—often on a monthly basis—due to the drug’s short half-life and lack of sustained release when injected into the vitreous. Various studies have thus concentrated on methods for achieving a more sustained release of bevacizumab, exploring alternative administrative routes such as suprachoroidal injection techniques [33], or employing nanobased drug delivery systems [1,5]. In their study, Sun et al. prepared mesoporous silica nanoparticles loaded with bevacizumab and reported encapsulation and drug loading efficiencies of 70.4% and 79.2%, respectively [38]. They found that MSN encapsulation was able to effectively preserve the bevacizumab in the vitreous/aqueous humor, maintaining its drug concentration; avoid tissue toxicity; suppress vascular endothelial growth factor-induced endothelial cell proliferation, migration, and tube formation in vitro; and provide sustained inhabitation of corneal neovascularization and retinal neovascularization in vivo. As MSN drug encapsulation presents as a promising DDS for intraocular neovascular diseases, future research should focus on testing this approach using different antiangiogenic therapy agents.

In another study, Pavia et al. (2021) [56] also looked at the application of mesoporous silica nanoparticle encapsulation. They incorporated tacrolimus (TAC) into silica nanoparticles functionalized with 3-aminopropyltriethoxysilane (MSNAPTES) as a potential treatment for general posterior and anterior segment eye diseases They investigated the applicability and safety of the systems through in vitro and in vivo studies, reporting that the MSNAPTES achieved up to 7% TAC loading. After looking at the vitreous cavity injection of the MSNAPTES over 15 days, no retinal impairments or optical nerve atrophy were observed, thus confirming the application of MSNAPTES as a promising and effective carrier for TAC for the treatment of ocular diseases.

Lastly, Wu et al. (2020) [40] were the first at the time to look into using mesoporous silica nanoparticles for drug delivery of mitomycin C to prevent postoperative pterygium recurrence. Wu and collaborators coupled low-density lipoprotein (LDL) with mesoparticles loaded with mitomycin C (MMC) (MMC@MSNs-LDL) for the inhibition of pterygium subconjunctival fibroblasts. They found the MMC loading efficiency to be 6% and that the MMC@MSNs-LDL had effective MMC targeting, thus inhibiting abnormal proliferation. Wu and collaborators reported that the MMC@MSNs-LDL exhibited less toxicity compared to normal fibroblasts, further emphasizing it as a precise DDS. Future studies should focus on evaluating the long-term effect and safety of this drug carrier in animal models.

Nanoporous polymers are different types of polymers, such as nylon, polyethylene, and polyester, that consist of a framework of pores with sizes below 200 nm [57]. They take on unique physical and chemical properties unlike other materials, such as thermal stability, hardness, conductivity, and a large surface area which helps enhance their ability to absorb molecules, such as drugs. Due to their low cost, biocompatibility, and biodegradable properties, these materials have been especially studied in polymeric DDS [58,59,60,61].

In one study, He et al. (2021) [41] developed a dosage-controllable drug delivery implant, designed for placement within the vitreous cavity. This implant consisted of a nanoporous PLGA capsule and light-activated liposomes, specifically for delivering methotrexate (MTX). Using pulsed near-infrared (NIR) laser both in vitro and in vivo, they were able to achieve controllable MTX releases, with release patterns following zero-order kinetics for the 1000 μg dose and first-order kinetics for the 500 μg dose. They observed that the drug releasing behavior was consistent between the in vitro and in vivo settings. Importantly, histological analyses revealed no abnormalities in the eyes or evidence of cytotoxicity, immune responses, or foreign body reactions after implantation into the vitreous cavity and treatment, thereby attesting to the safety of this ocular delivery system.

Nanoporous nanofibers are materials with a nanoscale structure and porous architecture. They are produced through electrospinning, a process where a polymer solution is exposed to an electric field, which causes the fibers to stretch and form their unique fibrous structure [62]. The porous architecture which also results from this fabrication approach can take on a variety of forms, ranging from close-pore structures to open-pore structures [63].

While research using nanoporous nanofibers as DDS is still very new and limited, in one recent study, Rohde et al. (2022) [42] investigated the potential applications of nanofibrous electrospun scaffolds, consisting of polymers, as a new DDS system for overcoming the limitations of liquid and semi-solid formulas, which are the most common drug delivery systems of ophthalmic diseases. They investigated this system specifically as a drug release system delivering gentamicin and dexamethasone for bacterial conjunctivitis. They found that when the nanofibers came in contact with the ocular surface, they dissolved the tear fluid. They also found that compared to the current models used for this type of drug delivery, the new system showed higher dosing accuracy and drug recovery. Subsequent analyses showed that gentamicin released from the fibers inhibited the growth of disease-specific bacteria and showed full antibacterial activity over a 12-week shelf-life period. After assessing the system in a porcine ex vivo microfluidic cornea model, they found a significantly prolonged ocular residence time compared to a conventional eye drop.

In another study, Li et al. (2023) [43] designed and developed a class of nanoporous, nanofibrous membranes loaded with celastrol for a sustained release and with hyaluronic acid to prevent burst release using electrostatic spinning. After placing the film directly in the subconjunctiva after injury, the membranes appeared to inhibit subconjunctival fibrosis. As celastrol was recently found to induce autophagy [64], a promising novel therapeutic target in various diseases, the researchers further hypothesized that celastrol could be a therapeutic option for the long-term development of antifibrotic drugs. These antifibrotic drugs may potentially help prevent tissue fibrosis following filtrative glaucoma surgery (e.g., trabeculectomy), a procedure aimed at reducing intraocular pressure (IOP) in glaucoma patients. Further analyses showed that celastro indeed triggered autophagy and promoted the expression of LC3A, LC3B, and Beclin-1 and that celastrol induced autophagy by inhibiting the PI3K/Akt/mTOR kinase complexes. After finding that celastrol decreases the expression and signaling of TGF-beta1, which is part of the signaling complex TGF-beta1/Smad2/3, a key role in fibrosis, the researchers concluded that celastrol inhibits subconjunctival fibrosis by inducing autophagy through inhibiting the PI3K/Akt/mTOR signaling and potentially also the TGF-beta1/Smad2/3 signaling pathway.

While nanoporous nanofibers find many of the same applications as other porous structures due to their unique porous structure, such as filtration, catalysis, sensors, energy storage, etc., they also have the additional advantageous properties of nanofibers, such as flexibility and a lightweight build, which make their use in ocular DDS very effective [65].

Advancements in nanotechnology within the past decades have made great strides in improving treatments for ocular diseases, from improving drug bioavailability to decreasing eye irritation and improving ocular biocompatibility [66,67,68,69]. As mentioned in the previous section, nanocarriers present as promising tools for drug delivery due to their uniform distribution, stability, high drug load capacity, enhanced biocompatibility, biodegradability, controlled release, increased cellular update, manufacturing ease, and cost effectiveness [1]. Nanoporous materials, in particular, further enhance these characteristics of nanocarriers, since their porous structure allows for even greater drug loading capacity, more precise control of drug release over extended periods, and protection of the encapsulated drugs from degradation [2].