Nanotechnology-Enhanced Phytopharmaceuticals for Ocular Health

Tripti Kshatri¹, Ravi Parashar², Preeti K. Suresh^3*

^1,2,3University Institute of Pharmacy, Pt. Ravishankar Shukla University,

Raipur (Chhattisgarh), India-492010

 ¹triptikshatricom9@gmail.com, ²raviparashar.prsu@gmail.com, ³suresh.preeti@gmail.com

 

Abstract

Phytomedicines have a long history of therapeutic use. A wide range of phytoconstituents, including alkaloids, flavonoids, glycosides, tannins, terpenoids, peptides, carbohydrates, and lipids, have demonstrated significant therapeutic properties. The medicinal benefits of plant extracts, their separated fractions, and pure phytoconstituents have been well documented, especially through in vitro studies. However, translating these in vitro results into effective in vivo applications and successful clinical trials poses substantial challenges. These challenges include issues related to standardisation, limited efficacy against severe diseases, inconsistent biological activity, and potential interference from complex phytoconstituents, especially for ocular drug delivery applications. To address these issues, there has been a shift toward ocular drug delivery using nanoscale phytomedicine. Innovative nanotechnology-based delivery systems are being extensively researched to solve these problems. Systems that deliver various phytoconstituents at the nanoscale can improve bioavailability, minimise side effects, and reduce necessary doses. This review will focus on nanotechnology-based delivery systems for phytomedicines in different ocular therapies, with an emphasis on lipid-based nanoparticles, nanomicelles, polymeric nanoparticles, and nanostructured lipid carriers, used for a range of ocular conditions.

Keywords: phytomedicine, nanomedicine, ophthalmic, nanotechnology, phytoconstituents

1. Introduction

Cataract, glaucoma, ocular trauma, dry eye syndrome (DES), age-related macular degeneration (AMD), conjunctivitis and eye inflammation are some of the most prevalent ocular disorders with high risk of visual loss and blindness, posing a huge clinical burden globally (Starvaggi et al., 2025a). Although the development of ophthalmic formulations has gained momentum, conventional therapeutic approaches to eye diseases (eye drops, oral/parenteral administration, and intravitreal injection) remain challenging because of low drug bioavailability and loss through the cornea, conjunctiva, blood-retina barrier, and vitreous dynamics (Ahmed et al., 2023). The conventional formulations may require frequent administrations leading to poor patient compliance and effectiveness.

Nanotechnology-based drug delivery systems may be employed to address these issues by offering high retention rates, drug targeting and controlled delivery in the eye (Li et al., 2023). Similarly, natural phytoconstituents, including flavonoids, alkaloids, glycosides, polyphenols, tannins and terpenoids (including, saponins, cardiac glycosides and sterols) in plants have gained prominence due to their diverse biological activities, including anti-inflammatory, anti-oxidant, anti-angiogenic, neuroprotective properties. But, their low water solubility, potential for deactivation, low stability and poor penetration limit the therapeutic potential and growth of therapeutic products containing these phytoconstituents (Duziegielewska et al., 2025).

While earlier studies have reported nanotechnology-based drug delivery for ocular applications independent of phytoconstituent-based drugs, a gap remains in integrating these two fields to overcome challenges in ocular drug delivery. Furthermore, current reviews generally lack mechanistic insight into the role of nanocarriers in improving the bioavailability of phytoconstituents across various ocular barriers, and into the comparative performance of nanoplatforms specifically designed to deliver phytomedicine-based ophthalmic formulations. To overcome this knowledge gap, this review offers a systematic assessment of nanotechnology-based phytopharmaceutical approaches for ocular drug delivery. In particular, this review critically evaluates major classes of bioactive phytoconstituents and their role in ocular diseases, discusses the design and functional merits of various nanocarriers (such as lipid-based nanoparticles, nanomicelles, polymeric nanoparticles and nanostructured lipid carriers) for improving ocular bioavailability of phytoconstituents, and provides insights into mechanisms, translational considerations and emerging clinical opportunities. This review will provide a new perspective on integrating phytomedicines with cutting-edge nanocarriers to develop next-generation, sustained, targeted, and efficient ophthalmic treatments.

Figure 1: Major plant-derived bioactive compounds for treatment of various ocular disorders

 

2. Bioactive phytoconstituents for interventions in ocular disorders

Plant-derived phytoconstituents are emeging as a class of therapeutic agents in ophthalmology, with antiangiogenic, neuroprotective, antioxidant, and anti-inflammatory properties (Karakus & Caliskan, 2021). Quercetin, a flavonoid found in Ginkgo biloba and Allium cepa, shows antihistaminic and antioxidant effects beneficial for dry eye disease and conjunctivitis, and it also protects retinal cells against oxidative stress in the treatment of diabetic retinopathy (Ikonne et al., 2020). Curcumin, a polyphenol found in Curcuma longa, exhibits anti-inflammatory activity, reducing retinal inflammation and corneal infection (Franzone et al., 2021). Lutein and carotenoids, found in Tagetes erecta and Spinacia oleracea, display antioxidant activity and help reduce ocular injury (Zhao et al., 2022). Resveratrol, a polyphenol found in Vitis vinifera, exhibits neuroprotective and antiangiogenic effects, thereby reducing retinal neovascularisation in the treatment of diabetic retinopathy (Bryl et al., 2022). Berberine, an isoquinoline alkaloid found in Berberis vulgaris, exhibits anti-inflammatory and antibacterial effects, making it useful in the treatment of conjunctivitis (Khan et al., 2016). Epigallocatechin gallate, found in Camellia sinensis, exhibits antioxidant activity and reduces oxidative damage used in treating age-related macular degeneration (Prasanth et al., 2019). These bioactive phytoconstituents protect ocular anterior and posterior segments by neutralizing reactive oxygen species and maintaining retinal integrity (Kumar & Talwar, 2024). Figure 1 depicts the major plant-derived bioactives from medicinal plants providing therapeutic effects across a range of ocular conditions.

2.1  Flavonoids

Polyphenolic compounds, especially flavonoids, exhibit a broad spectrum of biological activities, including antioxidant, free radical scavenging, antiviral, antibacterial, anti-inflammatory, anti-allergic, and anticarcinogenic effects, as well as antiplatelet, antithrombotic, and vasodilating properties (Cetin, 2021). Oxidative stress, inflammation, and reduced antioxidant capacity in ocular tissues significantly impact the onset and progression of eye conditions (Hsueh et al., 2022). Flavonoids antioxidant, anti-inflammatory, and ocular blood flow-promoting properties make them highly useful for eye health and treating eye disorders (Shen et al., 2023). Most flavonoids are poorly water-soluble and have limited bioavailability. Developing effective ocular drug delivery systems for direct flavonoid administration is crucial (Cetin, 2021). Such approaches can enhance the ability of flavonoids to reach the target sites within the eye and improve their ocular bioavailability (Krstic et al., 2021). Additionally, because flavonoids are sensitive antioxidants, nano-sized formulations have emerged as promising carriers for their preservation, enhanced bioavailability, and increased therapeutic efficacy (Kilinc & Acar Kuru, 2025).

2.2 Alkaloid

Alkaloids are nitrogen-containing bioactive compounds with a wide range of biological activities, including antioxidant, free radical scavenging, vasodilatory, antibacterial, anti-inflammatory, anti-allergic, and neuroprotective effects (Dubey et al., 2023). These properties benefit ocular conditions such as uveitis, dry eye disease, conjunctivitis, age-related macular degeneration, and glaucoma (Maiuolo et al., 2022). Conventional ophthalmic alkaloid preparations have limitations like low corneal permeability, poor aqueous solubility, short half-life, and rapid precorneal elimination (Baldim et al., 2020). To overcome these limitations, developing a nanocarrier-based drug delivery system is an effective approach, since they can enhance alkaloids' ability to reach the internal structures of the eye and improve their ocular bioavailability (Razavi et al., 2022).

2.3 Glycosides

Glycosides are naturally occurring bioactive compounds derived from plants that consist of sugars linked by a functional group (Kowsalya et al., 2025). The terms O-glycoside, N-glycoside, C-glycoside, and S-glycoside describe glycosides based on their glycosidic bonds (Fischer & Pedersen, 2025). Glycine refers to the sugar part of the glycoside, while aglycone is the non-sugar component. Glycosides exhibit a broad spectrum of biological activities, such as anti-inflammatory, anti-angiogenic, and antioxidant effects (Kowsalya et al., 2025). These properties are beneficial for ocular conditions like age-related macular degeneration, uveitis, diabetic retinopathy, and retinal ischemia (Oshitari, 2023). Conventional ophthalmic glycoside preparations have limited permeability across the anterior and posterior segments of the eye, face enzymatic degradation, and have poor aqueous solubility (Conte et al., 2025). To address these challenges, developing nanocarrier-based drug delivery systems is an effective strategy (Santos et al., 2025).

2.4 Terpenoids

Terpenoids, also known as isoterpenoids are a structurally diverse class of natural hydrocarbons characterised by a  wide-array of cyclic and acyclic carbon skeletons derived from the repetitive assembly of five-carbon isoprene units and are one of the most abundant groups of plant-derived compunds, (Maswal et al., 2023). Terpenoids are categorized on the basis of number of constitutent five-carbon isoprene units ranging from hemiterpenoids (C5), monoterpenoids (C10), to more complex sesquiterpenoids (C15), diterpenoids (C20), triterpenoids (C30) and tetraterpenoids (C40) (Mabou & Yossa, 2021). These bioactives exhibit a wide range of biological activities, including antioxidant, antimicrobial, anti-inflammatory, and neuroprotective effects (Câmara et al., 2024). These properties are reported to benefit ocular conditions such as age-related macular degeneration, dry eye disease, conjunctivitis, uveitis, diabetic retinopathy and glaucoma (Cheng et al., 2021). Conventional ophthalmic terpenoid preparations have limitations like low corneal permeability,  chemical instability, poor aqueous solubility, short half-life, and rapid precorneal elimination (Batur et al., 2024). To overcome these limitations, developing a nanocarrier-based drug delivery system is an effective approach (Davodabadi et al., 2025; Ashfaq et al., 2023).

2.5 Tannins

Tannins are polyphenolic biomolecules that include carboxyl and hydroxyl groups. They are reported to display a wide range of biological activities, such as astringent, antimicrobial, antioxidant, free radical scavenging, antibacterial, anti-inflammatory, and anti-allergic effects (Al-Shuhaib & Al-Shuhaib, 2025). These properties benefit ocular conditions like keratitis, diabetic retinopathy, dry eye disease, conjunctivitis, age-related macular degeneration, and glaucoma (Caban et al., 2022). Conventional ophthalmic tannin preparations face limitations such as large molecular size, instability, low corneal permeability, poor aqueous solubility, short half-life, and rapid precorneal elimination (Shree et al., 2024). To address these issues leading to poor ocular bioavailability, developing a nanocarrier-based drug delivery system is an effective strategy.

2.6 Proteins and bioactive peptides

Proteins and bioactive peptides exhibit a wide range of biological activities, including antioxidant, regenerative properties, free radical scavenging, antibacterial, antimicrobial, anti-inflammatory, anti-allergic, and neuroprotective effects (Shahidi & Saeid, 2025). These properties are reported to benefit ocular conditions such as diabetic retinopathy, antioxidant uveitis, corneal injury, dry eye disease, conjunctivitis, age-related macular degeneration, and glaucoma (Cheng et al., 2020). Conventional ophthalmic preparations of proteins and peptides have the inherent limitations, including low corneal permeability, enzymatic degradation, poor aqueous solubility, a short half-life, and rapid precorneal elimination (Shastri et al., 2023). Nanocarriers facilitate the targeted delivery  of proteins and peptides by overcoming the physiological barriers and improving their ocular bioavailability (Gorantla et al., 2020). Table 1 provides a summary of the major phytoconstituents utilised in the clinical management of ocular diseases.

Table 1: List of major phytoconstituents used in the clinical management of ocular diseases

S. No.	Active(s)	Category	Mechanism of Action	Disease	Ref.
1.	Quercetin	Flavonoid	Reduces the release of IL-6 and IL-10 in human corneal epithelial and conjunctival cells in a dose-dependent manner	Dry eye	(Caban et al., 2022)
2.	Rutin	Flavonoid	Controls blood flow and fortify the walls of blood vessels	Glaucoma	(Sim et al., 2022)
3.	Resveratrol	Polyphenol	Lowers intraocular pressure and has anti-inflammatory and neuroprotective qualities	Glaucoma	(Zhang et al., 2024)
4.	Esculin	Glycoside	Reduces refractive error, and improves uncorrected visual acuity	Cataracts	(Lin et al., 2022)
5.	Pterostilbene	Polyphenol	Reduces the expression of IL-6, IL-1β, and TNF-α, and inhibits oxidation and inflammation	Dry eye	(Favero et al., 2021)
6.	Isorhamnetin	Flavonoid	Reduces surface damage, TNF-α, IL-1β, and IL-8 expression, alleviate DED symptoms, and activate CFTR	Dry eye	(Wang & Chen, 2023)
7.	Luteolin	Flavonoid	Reduces IL-1β, IL-6, IL-18, and TNF-α in the corneal tissues, increases tear production, and repair corneal abnormalities	Dry eye	(Xie et al., 2023)
8.	Andrographolide	Terpenoids	Anti-hyperglycaemic, antioxidant	Diabetic retino-pathy	(Zhao et al., 2024)
9.	Castor oil	Lipid and fatty acids	Anti-inflammatory and antimicrobial properties	Eye inflamma-tion	(Sandford et al., 2021)
10.	Ellagic acid	Polyphenols	Antioxidant and inhibition of lipid peroxidation	Diabetic retino-pathy	(Li et al., 2023)
11.	Cinnamic acid	Phenyl propanoids	Anti-hyperglycaemic	Diabetic retino-pathy	(Yu et al., 2025)
12.	Acteoside	Phenyletha-noid glycoside	Aldose reductase, antidiabetic	Diabetic retino-pathy	(Taximaimaiti et al., 2023)
13.	Pycnogenol	Bioflavo-noids	Prevent damage to vascular endothelial cells caused by Aβ	Glaucoma	(Matos et al., 2020)

 

3. Bridging Ocular Barriers via Nanotechnology

Nanotechnology-based drug delivery systems have introduced a new paradigm in phytomedicine (Shanmugarathinam et al., 2025). Nanoparticles, nanoemulsions, nanosuspensions, liposomes, nanomicelles, nanodispersions, solid lipid nanoparticles, and nanostructured lipid carriers are among the nanoscale systems documented for the transport of phytoconstituents (Widyowati & Miatmoko, 2022). These nanoscale platforms accommodate phytoconstituents with varying degrees of lipophilicity and hydrophilicity, significantly enhancing their aqueous solubility and chemical stability (Ansari et al., 2026). By tailoring these nanoscale structures, modified release patterns can be achieved with improved therapeutic efficacy, reduced dosages, and fewer adverse effects (Khiev et al., 2021; Parvin et al., 2025). Furthermore, the high surface-area-to-volume ratio and their customisable dimensions may facilitate rapid dissolution and deep cellular penetration (Liu et al., 2023; Parvin et al., 2025). Nanotechnology-based systems, which operate through multifactorial mechanisms to enhance targetability, precision, and permeability, and possibly extended-release at the target site, are particularly valuable in ocular drug delivery (Bairagi et al., 2025). The integration of targeting ligands like transferrin or RGD peptides may further optimize the drug targeting (Nardella et al., 2025). However, the main challenge for clinical translation remain scaling-up the manufacturing process and concerns regarding long-term toxicity (Antonelli & Palma, 2025).

 Figure 2: Mechanisms of nanocarrier-mediated transport across ocular barriers for site-specific drug delivery

 

3.1 Nano-Ocular Drug Delivery Mechanisms

Topical ocular medications cross the corneal barrier through two primary routes, viz., the transcellular and the paracellular pathways (Kundu et al., 2025). The transcellular route involves drug transport through the corneal epithelial cells to reach the aqueous humour (Kundu et al., 2025). Still, this process may require chemical modification of the drug or assistance from the paracellular route, which involves the movement of drug particles through intercellular spaces and tight junctions (Lin et al., 2025). Figure 2 illustrates the mechanisms by which nanocarriers navigate complex ocular barriers (corneal, conjunctival, scleral, and retinal) afer instillation of eye drpos. The high surface-to-volume ratio of nanotechnology-based delivery systems facilitates enhanced interaction with the ocular surface, thereby extending ocular retention time (Wu, Tan, et al., 2023). This enhances drug targeting, gene delivery, transcorneal permeability, sustained or controlled release, reduces drug degradation, maximises contact time with the ocular surface, and helps overcome ocular barriers (Akhter et al., 2022).

Various phytoconstituents have been reported to suppress specific pro-inflammatory signals, indicating their potential in treating various diseases, including ocular conditions (Starvaggi et al., 2025). These naturally occurring actives can act through multiple pathways (Parveen et al., 2018). Studies indicate that the nanocarriers enhance posterior segment ocular bioavailability and also offer a controlled release pattern without causing discomfort in the eye (Cai et al., 2025); (Wang et al., 2021). Most known nanoscale systems are derived from synthetic or natural polymeric materials and lipids, and includes solid lipid nanoparticles, dendrimers, in situ hydrogels, cyclodextrins, liposomes, nanodispersions, niosomes, micelles, nanoparticles, and nanoemulsions (Razavi et al., 2022). These nanoscale platforms are engineered to incorporate both plant sourced phytoconstituents and  conventional synthetic drugs (Shree et al., 2024). The ideal features of phytoconstituent-loaded nanocarriers for ophthalmic conditions are illustrated in figure 3. To improve ocular retention, formulations are engineered with lipophilic characteristics, reduced particle size and mucoadhesive properties to adhere to the tear film and ocular mucosa, resisting rapid clearance caused by blinking and nasolacrimal drainage. Nanocarriers exhibit strong mucoadhesion and can effectively penetrate the tight junction of the corneal epitheilium and the  blood retinal barrier. In conditions such as diabetic retinopathy, these systems can inhibit pathological angiogenesis within the retina. Furthermore, the use of biocompatible materials ensures drug delivery without inducing irritation to the conjunctiva, cornea or retinal cells. Consequently, nanocarrier-based phytoconstituents achieve significantly higher concentrations at the target site compared to conventional eye drops.

Figure 3: Essential attributes of ideal ocular phytoconstituent-loaded nanoformulations

4. Nanocarriers in ocular phytotherapy

4.1 Phytosomes

Phytosomes are lipid-based delivery system characterised by a molecular complex between  phospholipids and bioactive phytoconstitutents. These are typically developed for phytoconstituents such as flavonoids, terpenoids, and tannins (Kumari et al., 2022). The lipid-lipid interaction between the formulation and the cell membrane facilitates the diffusion of the loaded phytoconstituent into the cell. In phytosomes, the molecules are covalently bound to the polar heads of the phospholipids (Kumar et al., 2020). Phytosomes are lipid nanocarriers that significantly increase absorption and bioavailability as compared to conventional herbal extracts (Priya & Kumaran, 2023). Abdelkader et al. (2016) developed lipidic phytosomes containing L-carnosine by dispersing phosphatidylcholine in hyaluronic acid or phosphate-buffered saline and delivering them to the lens using the solvent evaporation method. Using primary human corneal cells, the researchers assessed the phytosome formulations for cytotoxicity, size, zeta potential, shape, contact angle, spreading coefficient, viscosity, and ex vivo transcorneal penetration. Compared to a solution of hyaluronic acid and phosphatidylcholine, the L-carnosine-phospholipid complex had a size range of 380–450 nm, a polydispersity index of 0.12–0.2, and a viscosity 2.4–5 times higher. Ex vivo transcorneal permeation demonstrated regulated L-carnosine penetration into the cornea. High-sugar media incubated with and without L-carnosine pig lenses demonstrated a concentration-dependent significant suppression of lens brunescence in ex vivo experiments (Abdelkader et al., 2016).

4.2 Nanoparticles

Nanoparticles are  carriers with dimensions typically ranging from 1nm to 100 nm, and specifically designed nanoparticles have found applications for delivering medications to the eye (Joseph et al., 2023). They improve drug stability, extend the release of the drug, and consequently enhance its bioavailability (Tenpattinam et al., 2025). Nanoparticles designed for topical targeted drug delivery applications for the eye increase residence time, reduce toxicity, and lower medication loss and penetration through the cornea (Mobaraki et al., 2020). Topical ocular administration benefits from nanoparticles with enhanced transfection efficiency, controlled particle size, and a positive charge (Jacob et al., 2022). Advanced nanoparticulate-based ocular drug delivery platforms, are prioritizing the need to mitigate foreign body effect and ocular irritation, clinical advantages that have the potential to directly translate to increased patient compliance (Ashique et al., 2025). Cordeiro et al. (2021) developed and reported chitosan/hyaluronic acid nanoparticles with mucoadhesive properties aimed at targeting the  posterior segment of the eye. The formulated product could potentially reduce oxidative stress by incorporating antioxidant compounds. The nanoparticles were combined with actinoquinol, a UV-absorbing molecule, to enhance the reduction of oxidative stress. The nanoparticles exhibited a positive zeta potential, a polydispersity index of 0.220 ± 0.034, and a mean particle size of less than 400 nm. Pig eye sclera was used for ex vivo permeability testing. The ARPE-19 cells employed in cellular behaviour studies showed low cytotoxicity and indicated that the formulation effectively decreased oxidative stress. Additionally, the nanoparticles provided controlled delivery and strong ocular retention (Cordeiro et al., 2021). Chitosan nanoparticles loaded with quercetin and resveratrol, as well as chitosan nanoparticles modified with polyethene glycol (PEG) for enhanced delivery and synergistic effects on lowering intraocular pressure, as natural antioxidants for the treatment of glaucoma have been reported (Chung et al., 2020). The synthesised nanoparticles had a spherical form, entrapped resveratrol, and the loading efficiency declined as the PEG content increased. On the other hand, when PEG and bioactives were added, the particle size of the formulation increased. It was reported that adding quercetin to the mixture increased its ability to neutralise free radicals.

4.3 Nanomicelles

Nanomicelles are self-assembling nanoscale formulations with particle sizes ranging from 10 to 100 nm (Modi et al., 2025). Colloidal dispersions with a hydrophilic shell and a hydrophobic core are known as nanomicelles. The purpose of nanomicelles in ocular drug administration is to increase the solubility of actives that are insoluble in water (Liu et al., 2023). Nanomicelles increase ocular bioavailability, reduce medication degradation, improve corneal penetration, reduce adverse effects, and prevent irritation (Singh et al., 2025). Reshma et al. (2025) developed lutein loaded ploymeric nanomicelles with improved antioxidant activity for age-related macular degeneration. The nanomicells showed high drug entrapment of 84%, enhanced corneal permeation, minimal ocular irritation, prolonged ocular residence time overcoming lutein poor solubility and rapid ocular clearance. This study demonstrated that nanomicelles can enhance the ocular bioavailability and therapeutic efficacy of poorly soluble drugs (Shetty et al., 2025). Mengshuang et al. (2017) developed a curcumin-laden topical nanomicellar formulation with a polyvinyl caprolactam–polyvinyl acetate–polyethene glycol (PVCL–PVA–PEG) graft copolymer for ocular administration in order to increase the solubility, stability, and effectiveness of loaded curcumin and produce an anti-inflammatory effect. It was reported that the curcumin-loaded nanomicelle formulation significantly improved cellular absorption and corneal penetration while exhibiting superior ocular tolerability in rabbits. When compared to the free curcumin solution, an enhanced anti-inflammatory activity was observed (Li et al., 2017).

4.4 Nanostructured Lipid Carriers

Nanostructured lipid carriers (NLCs) are second-generation lipid-based nanocarrier composed of solid lipid, liquid lipid and surfactant (Nayak et al., 2025). They are self-assembling nanoscale formulations with particle sizes ranging from 10 to 1000 nm (Haider et al., 2020). NLCs improve corneal penetration, regulate drug release, and improve the drug stability in ocular medication delivery (Razavi et al., 2022). Increased viscosity, gel or semi-solid NLC systems may extend the retention period on the ocular surface (Singh et al., 2025). Varela-Fernández et al. (2022) developed lactoferrin-loaded NLCs to overcome the poor stability and rapid precorneal elimination of lactoferrin and improve its ocular delivery.  The optimised formulation exhibited a nanoscale particle size (120 nm), low polydispersity, high encapsulation efficiency, enhanced ocular residence time and sustained drug release. The lipid-based nanocarrier improved the physicochemical stability of lactoferrin and showed promising potential for increasing ocular bioavailability and therapeutic efficacy in anterior segment eye disorders. This study highlighted NLCs as an effective and biocompatible platform for ocular protein delivery (Varela-Fernández et al., 2022).

4.5 Nanogels

Nanogels have numerous applications, including chemical crosslinking, physical self-assembly, and their use in drug delivery (Yin et al., 2020). Drug-loading mechanisms (such as physical encapsulation and electrostatic interactions) and release methods (such as diffusion, stimuli-responsive, and enzyme-triggered) are also explored (Delgado-Pujol et al., 2025). These gels offer significant benefits in overcoming the limitations of conventional drug delivery systems by providing improved drug stability, prolonged release, and high specificity (Xia et al., 2025). Xiang et al. (2025) developed a ROS-responsive dexamethasone-loaded nanogel that showed stimuli-responsive drug release, prolonged ocular surface retention, and significant inhibition of pathological blood vessel growth in animal models while maintaining good corneal safety. This approach highlights nanogels as effective for improving therapeutic outcomes and reducing dosing frequency in inflammatory ocular disease (Xiang et al., 2024). Figure 4 presents various nanotechnology based approaches for the management of ocular diseases. Furthermore, table 2 summarises specific plant-based nanoformulations for ocular conditions, detailing their mechanism of action, animal models used for the study and an assessment of their benefits and drawbacks.

Figure 4: Nanotechnology-based approaches for management of ocular diseases

Table 2: Nanoformulations based on plants for management of various ocular conditions

S. No.	Carriers	Drug	Particle size (nm)	Mechanism of Action	Advantages	Limitations	Disease/animal used	References
1.	Ocular Films	Tamarindus indica seeds	50-300	Film-forming and stabilising agent	Sustained drug release	Insertion difficulty	Glaucoma/ Rabbit	(Ahmed et al., 2024)
2.	Lipidic Nanocarrier	Quercetine	65-165	Protecting the retinal ganglion cells and cornea from oxidative damage	Better penetration	Drug Leakage	Glaucoma/ Mouse	(Medoro et al., 2025)
3.	Chitosan Nanoparticle	Hyaluronic acid	170-280	Controlled delivery	Enhanced absorption	Low stability	Glaucoma/ Bovine conjunctival tissue	(Mirkani et al., 2025)
4.	Lipidic Nanoparticle	Cyclo-dextrin	150-200	Elevated glutathione and superoxide dismutase levels	Controlled drug release	Aggregation	Glaucoma/ Bovine lenses	(Vora et al., 2019)
5.	Nano-phytosomes	Rutin	120-180	Enhanced antioxidant property	Improved solubility	Complex formulation	Glaucoma	(Kumbhar et al., 2024)
6.	Miceller Nanocarrier	Pluronic-F127 and curcumin	20-30	Reduction in loss of retinal ganglion cells	Targeted drug delivery	Toxicity risk	Glaucoma/ Mice	(Davis et al., 2018)
7	Chitosan Nanoparticle	Resveratrol and quercetin	180-220	Sustained drug release and better reduction in intraocular pressure (5.5 ± 0.5 mm Hg) in normotensive rabbits using PEG-modified chitosan nanoparticles loaded with quercetin and resveratrol	Mucoadhesive, enhanced permeability	Instability, aggregation	Glaucoma/ Rabbit	(Natesan et al., 2017)
8.	Chitosan Nanoparticle	Resveratrol	210-240	In normotensive rabbits, intraocular pressure decreased by 4.3 ± 0.5 mmHg for up to eight hours	High permeability	Stability issue	Glaucoma/ Rabbit	(Pandian et al., 2017)
9.	Lipidic Phytosomes	L-carnosine	120-200	Regulated corneal penetration and suppression of lens brunescence demonstrated by ex vivo transcorneal permeation	Good entrapment	Limited data	Cataract/ Porcine eye tissue	(Abdelkader et al., 2016)
10..	Nano-dispersion	Hesperidin	100-300	Effectively  penetrate the tissue of the cornea	High permeability	Poor stability	Age-related macular degeneration/ Rabbit	(Majumdar & Srirangam, 2009)

 

5. Preclinical and Clinical Evidence

Nanocarriers offer a viable tool to overcome poor corneal permeability and low ocular bioavailability issues (Gorantla et al., 2020). Despite the therapeutic promise of nano-phytoformulations for ocular delivery, the majority of the research has remained in the in-vitro and in-vivo stages, with limited clinical translation (Kaur et al., 2026). As summarised in Table 3, preclinical studies have demonstrated that herbal bioactives, including curcumin, quercetin, resveratrol and plant polysaccharides exhibit significant anti-inflammatory, antioxidant and neuroprotective properties. These are particularly effective against retinal disorders, ocular inflammation, and dry eye disease (Conte et al., 2025). Studies demonstrate that liposomes, polymeric nanoparticles, solid lipid nanoparticles, and nanoemulsion significantly enhance stability, and ocular permeation of these constituents (Patel et al., 2023). Trials with curcumin-based phytosomes and plant-derived vesicles (PDEVs) indicate promising potential for reducing retinal damage and inflammation in human model (Segneanu et al., 2026). Future efforts must prioritize clinical validation to bridge the gap between preclinical promise and standardized therapeutic efficacy.

Table 3: Translational Status of Phytoconstituents in Ocular Nanocarriers: Preclinical and Clinical Evidence

S. No.	Study type	Phyto-constituent/ Drug	Nanocarriers	Indication/ animal model	Outcomes	References
1.	Preclinical	Curcumin	Liposome/ Polymeric nanoparticles	Retinal disorders/ Rat model	Enhanced stability, antioxidant activity	(Patel et al., 2023)
2.	Preclinical	Quercetin	Solid lipid nanoparticles	Ocular inflammation/Rabbit model	Improved bioavailability	(Gorantla et al., 2020)
3.	Preclinical	Resveratrol	Nano emulsions/ NLC	Dry eye or retinal damage / Mouse model	Increased corneal permeation	(Das et al., 2022)
4.	Preclinical	Plant polysacc-harides (eg. chitosan alginate)	Polysaccharide based nanocarrier	General ocular delivery / Rabbit model	Enhanced ocular retention	(Yu et al., 2020)
5.	Preclinical	Curcumin	Phytosomes	Ocular delivery / Rabbit model	Improved drug stability and permeability	(Segneanu et al., 2026)
6.	Clinical	Curcumin	Phytosomes	Ocular inflammation or retinal damage / Human	Improved bioavailability	(Segneanu et al., 2026)
7.	Clinical	Plant-derived vesicles (PDEVs)	Natural nanovesicles	Ocular therapy / Human	Early-stage translation potential with emerging clinical evidence	(Segneanu et al., 2026)

 

6. Toxicological and Safety Considerations

In addition to their therapeutic potential, plant-derived bioactive agents, also have toxicity and safety concerns (Dwyer, 2023). Inherent challenges of poor aqueous solubility, chemical instability and rapid precorneal clearance, often necessitates high dosages and/or the use of complex carriers that can exacerbate ocular irritation and cytotoxicity (Liu et al., 2023). Investigations indicate that high levels of phytochemical compounds might lead to corneal damage, impairments of mitochondria, oxidative stress and inflammation reactions within ocular tissues structures (Ahmad & Ahsan, 2020). Other factors like the presence of impurities, solvents, pesticides and inconsistencies in phytochemical content are likely to produce adverse effects (Thakur et al., 2020). Consequently, studies emphasize the need for extensive safety profiling, including in vitro, ex vivo and in vivo tests including ocular irritancy studies, histological analysis, cell viability studies and retinal safety profiling (Bonneau et al., 2022). Regulatory agencies now advocate for standardized extraction, dose optimization, and chronic toxicity studies to ensure the clinical viability of botanical ocular therapeutics (Naik et al., 2023); (Krishnaswami et al., 2024).

Nanotechnology-based approaches ensure better bioavailability and target-specific delivery of phytochemicals, however they have critical safety concerns (Javed et al., 2020). Although nano-sized particles enhance cellular uptake, they also pose risks of non-specific distribution, leading to unintended organ accumulation and potential cell/molecular interactions (Ding et al., 2024). Both phytochemicals and nanoparticles used for encapsulation, whether lipids, polymers or inorganic materials must be evaluated for immunogenicity, metabolic fate and biodegradability (Oladipupo et al., 2025). Testing for cytotoxicity (e.g. MTT and LDH assays), genotoxicity (comet assay), hemocompatibility and immunotoxicity are essential components in the safety testing process prior to clinical translation (Ahmad et al., 2022). Furthermore, for long-term therapies, chronic toxicity assessments are a critical prerequisite.

7. Regulatory and commercialisation hurdles

The regulatory landscape for herbal nano-formulation remains complex, and is governed by two overlapping frameworks viz., those governing traditional herbal remedies and those regulating nanotechnology (Kumar, 2024). Many national regulatory bodies still lack standardized guidelines specially tailored for plant-based nano-therapeutic systems (Parvin et al., 2025). For instance, the European Medicines Agency (EMA) does not provide specific requirements for plant-based nano-formulation but it does provide general recommendation on the pharmaceutical application of nanotechnology (Ansari et al., 2026). Similarly, the U.S. Food and Drug Administration (FDA) continue to evaluate these products on a case-by-case basis, while addressing nanotechnology within pre-existing regulatory frameworks rather than creating standalone categories (Desai et al., 2025). Technical guidance often depends upon proxy models, for e.g. data requirements for liposomal products were shaped using innovative intravenous liposomal product as a model (Schlich et al., 2022). In Asian regulatory systems, such as the Traditional Chinese Medicine (TCM) standards, often provide more established pathways for the acceptance of herbal-based remedies (Fan et al., 2012). This discrepancy can lead to varied market opportunities and also present challenges for manufacturers as they must ensure global compliance, safety and effectiveness of their products (Gupta et al., 2024). As a result thorough research and collaboration with regulatory experts become essential for successful product development and commercialisation (Etaware et al., 2025). Future global harmonization efforts by organizations such as the International Council on Harmonization (ICH) may establish more uniform principles (Dawoud, 2025). In order to satisfy various international regulatory requirements, product developers must adopt a systematic and well-documented approach for product design and delivery. 

            Figure 5: Regulatory approval flow chart for plant-based nano-formulations

8. Challenges and future prospects

Overcoming the highly organised tissue architecture of the eye is the primary physiological and physical barrier (Khiev et al., 2021). These potent barriers lower the drug bioavailability of both topically and intraocularly administered medications, necessitating frequent drug administration (Wu et al., 2023). The ocular nanocarriers are reported to increase corneal penetration, enhance ocular bioavailability, and improve their retention within the eye (Akhter et al., 2022). Treatment of breast cancer using sonodynamic therapy, which is based on low-dose radiation combined with methylene blue and apigenin-coated gold nanoparticles have been reported (Neshastehriz et al., 2024). Only apigenin has been used as a reducing and coating agent in the manufacture of silver nanoparticles, with size control (Mohammadi & Amini, 2024). Silver nanoparticles coated with green-synthesised curcumin have demonstrated antimicrobial activity against a variety of Aspergillus and Candida species (Amini et al., 2023). For the synthesis of silver/gold nanoparticles, the various phytochemicals found in plants function as a reducing agent (Amini et al., 2023). Silver nanoparticles with a curcumin formulation have demonstrated strong antimicrobial activity in a synergistic manner (Mohammadi et al., 2021). However, there is a significant gap in the in vivo validation of the ocular nanoformulations. Although, a number of animal models are available, their standardization across the various nanoplatforms complicates the optimization of developed formulations. (Akhter et al., 2022). The current literature on herbals is predominantly preclinical, and hence establishing clinical efficacy through human trials is needed for therapeutic validation. The challenges encountered with drug delivery methods based on phytoconstituent-loaded nanoformulations are illustrated in Figure 6.

Figure 6: Challenges with the phytoconstituent(s) loaded nanoformulations

9. Global Market Presence of Phytopharmaceutical Ophthalmic Products

The ability to recognise the commercial market potential of plant-derived compounds has paved the way for the development of numerous innovative formulations (Nagarajan et al., 2025). It has been reported that globally almost 80% of the population use traditional medicine, according to the World Health Organisation (WHO)  (Ansari et al., 2025). The polyherbal formulations leverage synergistic interactions with enhanced clinical effectiveness (Omutindo Nyakayo, 2025). Addressing safety constraints, specifically regarding undesirable toxicities and side effects related to herbal medication, is a major concern for the broader clinical adoption of herbal medicines. Distinct  marker compounds serve as benchmarks for identifying and quantifying the therapeutic potency of herbs across different environmental and genetic variations (Nagarajan et al., 2025).

10. Conclusions

Plant-derived bioactives are an underutilized therapeutic reservoir for the management of complex ocular pathologies, including dry eye disease, glaucoma, cataracts, age-related macular degeneration, chronic inflammatory conditions, and diabetic retinopathy. Their complex pharmacological profiles characterized by potent antioxidant, anti-inflammatory, antimicrobial, and neuroprotective properties are uniquely suited to address the complexity of the pathophysiology of ocular diseases. Their clinical translation has, however, not been successful due to the underlying biopharmaceutical limitations, specifically poor aqueous solubility, low stability, high precorneal clearance and limited penetration across the blood-ocular barriers.

The integration of nanotechnology has emerged as an innovative solution to address these challenges. The advanced drug delivery platforms like nanoparticles, nanostructured lipid carriers, nanomicelles, and phytosomes, have demonstrated remarkable potential in improving the physicochemical stability, ocular residence time, intraocular permeability, and targeted delivery of phytoconstituents. By faciliatating controlled release and site-specific targeting, these nano-enabled systems minimize systemic exposure and adverse events with improved patient compliance. The synergies between phytopharmaceuticals and nanotechnology are not just an incremental development but represent a paradigm shift towards precision ophthalmology. However, to support preclinical evidence, several major challenges in translation research have been identified such as the need for clinical validation, feasibility for large-scale manufacturing, and long-term toxicology profiling. Furthermore, the lack of harmonized global regulatory standards for nano-phytomedicines creates a significant hurdle for commercialization.

The future research need to prioritize on four major aspects, viz., clinical validation to transition from in vivo models to robust clinical trials to establish definitive therapeutic efficacy, develop reproducible and scalable nanocarrier fabrication processes to ensure pharmaceutical quality, elaborate toxicological profiling and immunogenic assessments specifically for ocular tissues, and establishing regulatory harmonization to streamline the approval and clinical translation of phytopharmaceutical-loaded nano-formulations. As this interdisciplinary area advances, nanotechnology-based platforms for phytopharmaceuticals are poised to become clinically viable, safe, and targeted interventions.

Consent for publication

 Not applicable.

Conflict of interest

The authors declare no conflict of interest, financial or otherwise.

Acknowledgements

The authors thank Director, University Institute of Pharmacy and Centre for Herbal Drug Technology, Pt. Ravishankar Shukla University, Raipur, for providing the requisite facilities for this study. Pt. Sundarlal Sharma Library at Pt. Ravishankar Shukla University, Raipur, is gratefully acknowledged for providing access to online resources through ONOS.

 

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