Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 8, pp. 1287-1306 © Pleiades Publishing, Ltd., 2026.

ISSN 0006-2979, Biochemistry (Moscow), 2026. © Pleiades Publishing, Ltd., 2026.

1287

REVIEW

Inorganic Nanoparticles:

Applications in Ophthalmology

Ekaterina V. Popova

, Victoria E. Tikhomirova

1,a

*, and Olga A. Kost

Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia

e-mail: vetikhomirova@gmail.com

Received October 31, 2025

Revised March 6, 2026

Accepted March 14, 2026

Abstract— This review summarizes current data on potential applications of the main classes of inorganic

nanoparticles in ophthalmology, as well as their advantages and limitations, and systematizes data on the

most studied inorganic nanoparticles, including gold and silver nanoparticles, metal oxides (e.g., iron oxide,

zinc oxide), silica, and insoluble calcium salts. Particular attention is paid to their toxicity to eye tissues

and the use as carriers for encapsulation and controlled release of various biologically active substances,

such as antiglaucoma drugs, antibiotics, anti-inflammatory and antitumor agents. The review examines the

results of in  vivo experiments using nanoparticles, demonstrating their physiological effects, capacity to

increase the bioavailability of drugs, and ability to prolong their therapeutic effect.

DOI: 10.1134/S0006297925603909

Keywords: inorganic nanoparticles, drug delivery, ophthalmology

* To whom correspondence should be addressed.

INTRODUCTION

The eye is susceptible to numerous pathologies of

both the anterior and posterior segments, such as cat-

aracts, inflammatory diseases (blepharitis, conjuncti-

vitis, keratitis, uveitis), diabetic retinopathy, age-relat-

ed macular degeneration (AMD), optic nerve atrophy,

glaucoma, and others. Topical administration of drugs

in the form of eye drops remains the most common

and convenient option among available treatment

approaches. This method is simple, non-invasive, al-

lows self-administration, and typically requires lower

doses than systemic therapy, thereby minimizing the

risk of side effects. However, effective ocular drug

delivery, particularly to the anterior segment, is sig-

nificantly constrained by the eye’s unique anatomy

and physiology, resulting in low drug bioavailability.

Only a small volume of drug solution (approximately

30  µL) can be applied to the ocular surface, where it

is rapidly diluted by tears and cleared through the

nasolacrimal duct. Thus, less than 5% of a topically

administered dose reaches the intraocular tissues [1].

In addition, the cornea and the sclera/conjunctiva

present structural barriers that further limit drug

penetration into the anterior chamber. Drug diffu-

sion through the cornea is strongly influenced by its

physicochemical properties. The corneal epithelium is

negatively charged at physiological pH and contains

tight intercellular junctions, thus acting as the main

barrier to hydrophilic molecules. The stroma, which

is composed of collagen fibers and contains aqueous

pores, permits the passage of hydrophilic substanc-

es but restricts penetration of lipophilic compounds,

representing a secondary barrier to efficient drug de-

livery [2, 3].

Overcoming the ocular barriers to enhance the

efficacy of therapies for eye diseases can be achieved

through the use of diverse drug delivery systems, both

conventional (emulsions, ointments, suspensions, and

gels) and advanced [nanoparticles (NPs), liposomes,

dendrimers, nanomicelles, etc.] [2]. The growing in-

terest in inorganic NPs in ophthalmology is driven by

their controlled physicochemical properties, bioavail-

ability, and capacity to improve the drug delivery

efficiency  [2]. Due to the high specific surface area

and, consequently, the large proportion of surface

atoms, nanoparticles exhibit increased reactivity and

pronounced catalytic activity. At the nanoscale, these

POPOVA et al.1288

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

particles may also display altered optical properties,

reduced melting temperatures, increased mechanical

strength, and, in the case of ferromagnetic materials,

a transition to a superparamagnetic state. A key ad-

vantage of NPs in medical applications is their small

size, which enables them to cross cellular barriers.

On the one hand, this property offers significant po-

tential for targeted drug delivery; on the other hand,

it poses potential risks of toxicity. The mechanisms

of NP-induced toxicity are associated with oxidative

stress, mitochondrial dysfunction, DNA damage, and

disruption of the cell cycle. Furthermore, NP char-

acteristics such as size, shape, and surface charge

(ζ-potential) play critical roles in determining their

toxicity profiles.

NPs can serve both diagnostic and therapeutic

purposes in ophthalmology. They are effective carri-

ers for antimicrobial, antitumor, antioxidant, anti-in-

flammatory, and antiglaucoma drugs. In some cases,

NPs themselves exhibit therapeutic activity [2, 4, 5],

contributing to more targeted and efficient treatment.

NPs can enhance the permeability of ophthalmic bar-

riers, prolong drug residence time on the eye surface,

enable targeted delivery to specific tissues, and sup-

port sustained drug release  [2]. Positively charged

NPs have a high affinity for the corneal surface due

to electrostatic interactions with negatively charged

mucins. Negatively charged or neutral particles small-

er than 500  nm can diffuse through the vitreous

body (the pore size of the central vitreous mesh is

~550  nm), while positively charged particles interact

with the vitreous body, leading to their immobiliza-

tion  [6]. While this ability can be advantageous for

creating a localized drug “depot” that allows pro-

longed release, it also restricts drug penetration into

deeper ocular layers, such as the retina  [7]. The pres-

ent review discusses the prospects and limitations of

using inorganic NPs in ophthalmology.

GOLD NANOPARTICLES

Gold NPs (AuNPs) are inert, highly biocompatible,

and capable of cellular uptake, enabling penetration

into deep ocular tissues [5, 8]. Their physicochemical

properties and, therefore, biomedical applications are

strongly influenced by the size, shape, and surface

charge. AuNPs can be synthesized across a broad size

range, from ultra-small particles (<2  nm) to structures

measuring several hundred nanometers [8, 9]. They

also exhibit diverse morphologies, including nano-

spheres, nanorods, nanocages, nanoshells, nanostars,

nanotriangles, and nanoclusters. The shape of AuNPs

is a major factor influencing their cellular uptake

[8]. For example, gold nanorods smaller than 10  nm

are widely utilized as biosensors and cancer thera-

py agents due to their enhanced cellular penetration

and efficient renal clearance. Nanostars selective-

ly accumulate in tumors and exhibit cytotoxicity at

high concentrations (200  µg/mL) [8]. The viability

of isolated human corneal epithelial cells decreased

when treated with polyethylene glycol (PEG)-modified

(PEGylated) AuNPs [6  ±  3  nm by transmission electron

microscopy (TEM); ζ-potential, not specified] at con-

centrations above 1  µM  [10]. Intravitreal injection of

spherical AuNPs (20  nm by TEM; ζ-potential, −36  mV)

at a concentration of 200  µg/kg body weight in rats

caused degenerative changes in the lens and cyto-

plasmic vacuoles and distortion of the cortical lens

[11]. These structural alterations were accompanied

by molecular changes, such as decreased aquaporin-0

expression and increased levels of tumor necrosis

factor-α, reactive oxygen species (ROS), and phosphor-

ylated non-receptor tyrosine kinases in lens tissue ho-

mogenates. Collectively, these effects may contribute

to a cataract-like pathology [11].

Due to the surface plasmon resonance phenom-

enon, AuNPs can be used as sensitive detectors for

pathogenic bacteria in the eye and for glucose in

tears in diabetes patients [12,  13], as well as contrast

agents in optical coherence tomography (OCT) and

photoacoustic imaging [9]. Owing to their ability to

absorb and scatter light, AuNPs (particularly those

larger than 40  nm) enhance visualization of ocular

structures and can support the diagnosis of retinal dis-

eases, glaucoma, and diabetic retinopathy [5, 9]. The

concentration of NPs required for effective contrast

varies depending on the target tissue and imaging mo-

dality. For instance, in OCT studies using ex  vivo pig

eyes, injection of gold nanorods (40×10  nm) into the

aqueous humor at a concentration of 1×10

  NPs/mL

(equivalent to 1.66×10

−9

  M) produced a measurable

signal and enabled visualization of aqueous outflow

from the anterior chamber of the eye  [9]. In  vivo

experiments in mice demonstrated that slightly larg-

er nanorods (45×13  nm) injected into the cornea and

anterior chamber could be detected at concentrations

as low as 1.2×10

−10

  M, yielding a threefold increase

in contrast [14]. Additionally, studies in rabbits have

shown that AuNPs can be employed in photo- and ul-

trasound-induced hyperthermia for cancer treatment

[15, 16].

The introduction of spherical AuNPs (8-12  nm

by TEM) at a concentration of 17  µg/mL into the cel-

lular environment of various pathogenic organisms,

combined with irradiation by a 400-nm femtosecond

laser, suppressed the growth of gram-negative bacte-

rium Escherichia coli, gram-positive bacteria Staph-

ylococcus aureus, Enterococcus faecalis, and Liste-

ria monocytogenes, and Candida albicans yeast [17].

In the absence of laser irradiation, AuNPs exhibit rel-

atively low antibacterial activity, which is primarily

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

attributed to physical interactions with the bacterial

surface. For particles smaller than 20  nm, quantum

surface effects also play a role, as a strong electric

field around the NPs can induce hyperpolarization

and structural damage in organic components of bac-

terial cell wall[18]. Through electrostatic interactions

with bacterial cells, AuNPs, like other NPs, can dis-

rupt the integrity of bacterial cell wall and cell mem-

brane without necessarily penetrating into the cell.

This interaction alters membrane potential, increases

permeability, and leads to the leakage of intracellular

content. Additionally, AuNPs can release Au

ions that

penetrate the cell wall and induce cell death via the

following three mechanisms: destruction of the cell

wall, induction of oxidative stress, and damage to in-

tracellular components [19].

The surface of AuNPs can be functionalized with

a wide range of ligands, including polymers, DNA,

peptides, RNA, and fluorescent molecules[5]. Non-co-

valent modification is achieved through electrostatic

interactions, where positively charged drugs are at-

tracted to the negatively charged surface of AuNPs.

Another method is covalent conjugation that involves

the formation of covalent bonds between AuNPs and

functional groups (-SH, -CN, -NH

, -COOH, and -OH)

present on antibodies, aptamers, proteins, peptides,

and small molecules [8,20]. Additionally, bifunctional

linkers can be used that contain a gold-binding group

at one end and biotin or streptavidin moiety at the

other [8].

Topical administration of eye drops with PEGylat-

ed AuNPs with a covalently attached naphthalimide

fluorophore [6  ±  3  nm by TEM; hydrodynamic di-

ameter (D

), 29  ±  1  nm; ζ-potential, not specified]

to excised rabbit eyes demonstrated rapid interac-

tion with the eye surface, with particle adhesion

observed within 3  min. At this time point, AuNPs

were already detectable in the stroma and lens, and

after 2  h, they were also present in the iris and ret-

ina [10]. Similarly, after instillation of uncoated and

hyaluronic acid-coated AuNPs (15-20  nm; 50  µg/mL)

into mouse eye, both types of NPs reached the reti-

nal pigment epithelium (RPE), but the coated particles

exhibited enhanced tissue penetration with approxi-

mately 50% higher tissue accumulation compared to

uncoated ones [21]. In mice, intravenously injected

AuNPs (50  nm) localized in the choroid and retina

and suppressed choroidal neovascularization after

laser-induced burn  [22]. In contrast, intravenously

injected smaller AuNPs (10  nm) failed to cross the

blood–retinal barrier (BRB). However, following fo-

cused ultrasound exposure, AuNPs were detected in

the eye tissues, with smaller NPs (10  nm by TEM;

, 59  nm; ζ-potential, −16.4  mV) being 16.9 times

more abundant than larger NPs (55  nm by TEM; D

83  nm; ζ-potential, −21.5  mV) [23]. In a mouse model

of type 1 diabetes, hexapeptide-functionalized spher-

ical AuNPs (18.5  nm by TEM; ζ-potential, −35.3  mV)

achieved greater retinal penetration following intra-

vitreal injection compared to the retro-orbital deliv-

ery. After intravitreal administration, NPs localized

to the superficial retinal layers at 6  h and to retinal

nerve fibers by 12  h  [24]. In mice with induced di-

abetic retinopathy, these AuNPs were preferentially

taken up by microglial and endothelial cells, which

reduced pathological neovascularization and retinal

hemorrhage due to the inhibition of endosomal acid-

ification. AuNPs suppressed the activation of MAPK

signaling and significantly downregulated expression

of proinflammatory factors, including interleukin 1β,

interleukin  6, and cytokine MCP-1, as well as the ad-

hesion molecules ICAM-1 and VCAM-1, in the mouse

retina [24]. The above data confirm the ability of

AuNPs to cross various anatomical and physiological

barriers, making them promising carriers for drug

delivery.

The incorporation of the flavonoid quercetin in

two types of gold particles– AuNPs (up to 10  nm) and

gold “yarn” composed of individual threads measur-

ing 17×50  nm (average diameter, 300  nm) – showed

that the loading efficiency of the “yarn” was two

times higher and amounted to 40%. The drug was

slowly released from the “yarn” over a period of 15

days[25]. When quercetin (1  mg/mL) was incorporat-

ed into the gold “yarn” and applied to the RPE cells

subjected to sodium iodate-induced oxidative stress, it

preserved cell viability at up to 96%, while in the ab-

sence of quercetin, 98% of cells died[25]. In  vivo stud-

ies in mice with sodium iodate-induced AMD showed

that intravitreal administration of quercetin-loaded

gold “yarn” (100  mg/kg) effectively preserved retinal

structure and thickness at the levels comparable to

those in healthy controls. While free quercetin pre-

vented the formation of retinal protein deposits on

day 7 following oxidative stress, this effect was not

sustained on day 14. In contrast, quercetin delivered

via gold “yarn” prevented deposit formation even at

day 14, likely due to its prolonged release [25].

AuNPs show significant promise in gene therapy

of hereditary retinal diseases. For instance, AuNPs

surface-modified with plasmid DNA have demonstrat-

ed high transfection efficiency in RPE cells, compara-

ble to that achieved with liposomes [26].

AuNPs can also be used for enhancing refractive

power and increasing image contrast of contact lenses

[27]. Contact lenses incorporating AuNPs hold poten-

tial for treatment of ocular cystinosis [28], protection

of eyes from laser and ultraviolet (UV) radiation[29],

and compensation for color vision deficiencies [30].

The incorporation of AuNPs into contact lenses also

improved the loading efficiency for ophthalmic

drugs such as the β-adrenergic blocker timolol [31],

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

the antihistamine ketotifen [32], and the prostaglan-

din analog bimatoprost [33], with drug incorporation

directly correlating with the NP content in the lens

[31-33]. Lenses containing AuNPs exhibited signifi-

cantly slower drug release compared to conventional

lenses[31-33], with ketotifen and bimatoprost remain-

ing detectable in the tear fluid of rabbits even 72  h

after lens application [32, 33]. Moreover, after just

one day of wearing timolol-loaded NP lenses, rabbits

showed a fourfold increase in the drug concentration

in the ciliary muscle and a twofold increase in the

conjunctiva compared to lenses without NPs [31].

SILVER NANOPARTICLES

Silver NPs (AgNPs) exhibit pronounced antibacte-

rial activity. While metallic silver is largely inert, in

tissues, it ionizes due to the presence of oxygen and

body fluids, releasing biologically active Ag

ions that

induce oxidative stress in microbial cells[34]. Inaddi-

tion, AgNPs exert antibacterial effects through direct

physical interaction with bacterial cell walls of both

Gram-negative and Gram-positive bacteria and promo-

tion of ROS generation. AgNPs and silver ions interact

with exposed sulfhydryl groups of bacterial proteins,

disrupting DNA replication[35]. Interaction with bac-

terial DNA further inhibits replication, leading to the

cell cycle arrest in a phase similar to G2/M, ultimate-

ly causing cell death through oxidative damage [19].

Additionally, AgNPs reduce the expression of efflux

pump genes[35] and interfere with the quorum sens-

ing in bacteria by suppressing key genes (lasI/lasR,

rhlI/rhlR), thereby impairing biofilm formation [36].

AgNPs smaller than 30  nm have been shown to

exhibit stronger antibacterial effects than larger par-

ticles, with cubic, plate, and rod-shaped NPs demon-

strating greater antibacterial activity than spherical

ones [37]. The antibacterial properties of AgNPs can

be enhanced by combining them with photosensitiz-

ers – compounds that, under illumination at specific

wavelengths in the presence of molecular oxygen,

generate ROS (singlet oxygen, superoxide, hydroxyl

radicals)[38-40]. For example, a nanosystem based on

a metal-organic framework containing AgNPs and the

photosensitizer chlorin E6 (D

, 211  nm; ζ-potential,

−19.7  mV) demonstrated significant antibacterial ac-

tivity when applied to the ocular surface. In a slight-

ly acidic microenvironment characteristic of corneal

infections, the system released Ag

ions along with

the photosensitizer, inducing oxidative stress in both

Gram-negative and Gram-positive bacteria and inhib-

iting biofilm formation. In murine models of induced

keratitis, this nanosystem was more efficient than the

commercially available antibiotic levofloxacin [38].

AgNPs functionalized with synthetic polymers to im-

prove biocompatibility and prevent aggregation [41],

as well as to enhance their targeting specificity [42],

exhibit a broad-spectrum antibacterial activity. This

includes effectiveness against antibiotic-resistant

strains such as methicillin-resistant S.  aureus[41] and

multidrug-resistant Pseudomonas aeruginosa [42].

Consequently, AgNPs can be used to treat infections

of the conjunctiva, cornea, and lacrimal pathways, in-

cluding bacterial keratitis [37, 40].

In the case of human corneal epithelial cells,

AgNPs (D

, 100  nm and 230  nm; ζ-potential, not spec-

ified) were found to be safe at concentrations up to

5  µg/mL. These concentrations did not impair cell

proliferation but did limit cell mobility [43]. Treat-

ment of human corneal epithelial cells with AgNPs

also markedly increased expression of the angioten-

sin-converting enzyme  2 (ACE2) gene and moderate-

ly upregulated the gene encoding membrane-bound

serine protease  2; however, this effect did not trans-

late into higher protein levels [43]. Pretreatment of

cells with 5  µg/mL AgNPs mitigated the proapoptotic

effect of UV irradiation by reducing the expression of

proapoptotic proteins (caspases  8 and  9, BAX, PUMA)

and the inflammatory cytokine interleukin  6 [43].

At higher AgNPs (20  nm) concentrations (≥25  µg/mL),

the viability of human corneal epithelial cells was

significantly reduced and their migration rate slowed,

likely due to the inhibition of α-smooth muscle actin

expression [44]. Atthe same time, topical application

of AgNPs at concentrations of 10 and 250  µg/mL in

rabbits with corneal ulcers caused no histopatholog-

ical changes in eye tissues, with NPs penetrating all

layers of the cornea, including the corneal epitheli-

um, stroma, and endothelium [44].

Anisotropic AgNPs, including rods (96×12  nm;

ζ-potential, −22.3  mV) and triangles (side length,

90  nm; ζ-potential, −20.6  mV) at a concentration of

5×10

  particles/mL caused greater damage to rab-

bit corneal cells compared to isotropic forms, such

as spheres (radius, 26  nm; ζ-potential, −19.8  mV)[37].

Cell viability after treatment with spherical NPs re-

mained above 80%, whereas triangles reduced viabil-

ity to >68% and rods to >25%, indicating that rod-

shaped NPs are the least biocompatible form of AgNPs

[37]. Anisotropic AgNPs also induced DNA damage,

suggesting they can penetrate into cells as deep as to

the nucleus. The cytotoxicity is further influenced by

the NP concentration and size (the smaller the size,

the higher the penetration of NPs into the cell and

the greater the toxic effect)  [45]. It has been shown

that AgNPs can translocate into the central nervous

system, compromising the blood-brain barrier, and

can enter via afferent neural pathways, visual routes,

or direct cellular uptake. This can trigger inflamma-

tory responses by activating glial cells, leading to the

release of proinflammatory cytokines, ROS, and nitric

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

oxide, which may contribute to the development of

neurodegenerative disorders even upon topical NP

administration to the eye [46].

The anti-inflammatory effect of AgNPs (17  ±  3nm

by TEM; ζ-potential, −4.8  mV) was demonstrated via

intravitreal administration of 0.025  µg NPs into the

eyes of mice simultaneously with inflammation in-

duction. NPs at concentrations up to 50  µg/mL did

not affect cell viability or rhodopsin gene expression

in retinal tissue [47]. Beyond their anti-inflammato-

ry activity, AgNPs exhibit antiangiogenic properties

and suppress neovascularization  [34, 37], suggesting

potential applications in the treatment of retinal

disorders, such as diabetic retinopathy and AMD.

AgNPs inhibit angiogenesis by modulating the PI3K/

Akt signaling pathway, a key intracellular cascade

controlling cell growth, proliferation, and survival,

thereby reducing the viability of retinal endothelial

cells. The antiangiogenic effect depends on the NP

shape: when rod-shaped NPs (96×12  nm; ζ-potential,

−22.3  mV) and triangular NPs (side length, 90  nm;

ζ-potential, −20.6  mV) at 5×10

particles/mL were

compared, more anisotropic shape exhibited stron-

ger effects both in  vitro (chorioallantoic membrane

of chicken embryos) and in vivo (rabbit eye) [37].

TITANIUM DIOXIDE NANOPARTICLES

Titanium dioxide NPs (TiO

NPs) are cost-effective,

easy to synthesize, and highly chemically stable [48].

They can be used as carriers of active substances

and can provide controlled drug release in response

to stimuli such as UV radiation or ultrasound [48].

UV radiation also activates the antibacterial proper-

ties of TiO

NPs (the photocatalytic effect), inducing

generation of ROS that disrupt bacterial cell walls

and cause denaturation of proteins and DNA [19].

On the other hand, TiO

NPs have been report-

ed to exhibit toxicity toward ocular tissues. Ex  vivo

treatment of corneal endothelial cells and in  vivo ex-

posure of mouse eyes to TiO

NPs (40-60  nm by TEM;

ζ-potential, not specified) at concentrations of 50 and

100  µg/mL resulted in corneal cell damage charac-

terized by increased numbers of deformed and dead

cells, reduced cell density, and decreased activity of

antioxidant enzymes, such as glutathione peroxidase

and superoxide dismutase (SOD), leading to oxidative

stress[49]. Higher concentrations of TiO

NPs further

elevated apoptosis rates in corneal endothelial cells

and increased the proportion of cells in the G2/M

phase of cell cycle [49]. Treatment with 1000 ng/mL

TiO

NPs slightly reduced the density of brain endo-

thelial cells in mice with endothelioma, with cell via-

bility measured at 83.8  ±  2.1% for 42  ±  3-nm NPs and

92.8  ±  3.7% for particles >1  µm. Exposure to these NPs

also caused degradation of claudin-5, a protein essen-

tial for the formation of tight intercellular junctions

between retinal endothelial cells, thereby impairing

their barrier function [50]. Moreover, TiO₂ NPs of

42  ±  3  nm administered intravitreally into the eyes

of mice at 0.25-0.5  ng/eye were able to penetrate into

the posterior segment, accumulate there, and induce

retinal damage [50]. Additionally, similar to AgNPs,

TiO

NPs have been implicated in the development

of neurodegenerative disorders [46].

At the same time, due to their cytotoxicity, TiO

NPs show potential as chemotherapeutic agents for

cancer treatment, particularly when combined with

UV radiation [51], which may have applications in

ophthalmology. The combined effect of TiO

NPs and

UV radiation (2.5  J/cm

) was shown to suppress pro-

liferation, migration, and metabolic activity of human

Tenon’s capsule fibroblasts, suggesting a promising

approach for reducing postoperative fibrosis in glau-

coma [52].

Functionalization of TiO

NPs offers a strategy to

mitigate their toxic effects. For example, modification

of TiO

NPs with glutathione reduced their cytotoxic-

ity toward Chinese hamster ovary cells by 37% while

enhancing cell proliferation by 60% compared to un-

modified NPs[53]. Incorporation of tadalafil in gluta-

thione-modified TiO

NPs (less than 10  nm by TEM;

, 46  nm; ζ-potential, −40.7  mV) ensured its slow re-

lease over several hours in  vitro [53]. These findings

indicate that TiO

NPs have significant potential in

ophthalmology for prolonging drug action.

Another interesting potential application of TiO

NPs in ophthalmology is doping of polymeric contact

lenses to increase their refractive index in order to

bring it closer to that of the cornea [54]. For this

purpose, TiO

NPs were dispersed at a concentration

of 0.005 (w/v) in solutions of polymethyl, polyhy-

droxyethyl, and polyglycidyl methacrylates in chloro-

form. The resulting lenses were highly transparent in

the visible range while effectively blocking UV light

(due to lower transmission values in the UV region),

with the highest optical clarity observed in lenses

doped with polyglycidyl methacrylate  [54].

ZINC OXIDE NANOPARTICLES

Zinc oxide (ZnO) NPs exhibit high chemical and

photostability, along with strong UV light absorption

capabilities [55]. ZnO NPs can be used for the deliv-

ery of biologically active substances and visualiza-

tion of tumors; they also possess selective cytotox-

icity to cancer cells [55, 56]. Furthermore, ZnO NP

suspensions (20-40  nm by TEM, 250  µg/mL) display

pronounced antifungal and antimicrobial properties

and can be used for contact lens storage solutions

POPOVA et al.1292

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

by inhibiting the growth of both Gram-positive and

Gram-negative microorganisms [57]. Similar to TiO

NPs, the antibacterial activity of ZnO NPs upon light

exposure is primarily attributed to the generation of

ROS, which disrupt bacterial cell walls [19]. In the

absence of light, ZnO NPs retain their antimicrobial

efficacy through the release of Zn

ions. They can

also downregulate bacterial genes involved in exo-

polysaccharide synthesis, which is essential for bio-

film formation, as well as genes regulating quorum

sensing in bacteria [36]. The antimicrobial activity of

ZnO NPs (~10  nm, 30-50  mg/mL) against common oc-

ular pathogens, such as S.  aureus and P.  aeruginosa,

is significantly enhanced by exposure to femtosecond

laser irradiation at 400  nm [58].

There is evidence that ZnO NPs adversely af-

fect human corneal epithelial cells at concentrations

≥5  µg/mL ex  vivo. ZnO NPs (50  nm, 5-250  µg/mL) ap-

plied to rabbit eye wounds caused corneal opacity

and significantly delayed wound healing [59]. Sim-

ilarly, ZnO NPs with a size of 9.8  nm showed tox-

icity toward human retinal epithelial cells with a

half-lethal dose of 11.3  µg/mL, while treatment with

20  µg/mL resulted in over 90% cell death [58]. At the

same time, ZnO NPs averaging 10.2  nm in diameter

and characterized by a narrower size distribution, a

more uniform spherical shape, and reduced aggrega-

tion, showed no cytotoxic effects in human RPE cells

at concentrations up to 20  µg/mL [58].

The cytotoxic effect of ZnO NPs can be exploited

therapeutically, for example, for exhibiting the antifi-

brotic activity[60]. ZnO NPs (irregularly shaped crys-

tals; D

, 56  nm; ζ-potential, −13.5  mV) inhibited the

migration and proliferation of human Tenon’s capsule

fibroblasts and induced their apoptosis via intracellu-

lar ROS accumulation. The effect was dose-dependent,

with ROS levels increasing approximately 3-5-fold

as NP concentrations rose from 0 to 16  µg/mL [60].

Treatment with ZnO NPs also significantly reduced

the expression of transforming growth factor beta

(TGF-β1, the most potent profibrotic cytokine) and

procollagen. The antifibrotic effect of ZnO NPs can

be used in preventing complications after glaucoma

surgery.

ZnO NPs (~30  nm by TEM; ζ-potential, not speci-

fied) containing a nutgrass (Cyperus rotundus) extract

were used to treat induced diabetic retinopathy in

rats [61]. Loaded ZnO NPs were administered oral-

ly to rats at 10  mg/kg body weight for 42 days. The

treatment increased the activity of antioxidant en-

zymes and reduced cytokine content (oxidative stress

marker). Additionally, insulin activity improved, re-

flecting zinc’s role in glucose homeostasis and dia-

betes pathogenesis [55]. Histopathological analysis

of retinal tissues revealed that untreated diabetic

retinopathy caused severe disruption of retinal cell

organization, whereas NP-treated retinas were more

uniform and structurally intact [61].

Finally, ZnO NPs can be used to cross-link colla-

gen hydrogels to improve their rheological properties

(hardness, adhesiveness, viscosity), as well as to slow

the release of incorporated drugs (e.g., dexametha-

sone) included in hydrogels [62].

MAGNETIC NANOPARTICLES

Magnetic NPs are most commonly iron oxides,

such as α-Fe

(hematite), γ-Fe

(maghemite), and

(magnetite), although pure metals (Fe, Co, and

Ni) can also be used. Like other NPs, magnetic NPs

can exhibit cytotoxicity, tend to aggregate and oxi-

dize, but they are biodegradable as part of normal

iron metabolism [63, 64]. Their antibacterial activity

arises from physical interactions with the cell wall,

induction of ROS, photothermal and photodynamic

effects, and disruption of bacterial efflux systems.

Atthe molecular level, they can damage proteins and

DNA and suppress the expression of virulence and

antibiotic-resistance genes [65]. The toxicity of mag-

netic NPs depends strongly on particle size, surface

coating, and administered concentration. For exam-

ple, a mixture of magnetite NPs coated with silica

and Zonyl™ FSA (fluorine-containing surfactant) at

concentrations up to 40  µg/mL showed no adverse

effects on photoreceptor cells or retinal function in

mice, whereas the viability of human RPE cells de-

creased by 25% already at 5  µg/mL NPs [66]. Sili-

ca-functionalized magnetite NPs (~200 nm by TEM;

, ~300  nm; ζ-potential, not specified) were non-cy-

totoxic to human retinal cells up to 100  µg/mL [67].

Iron oxide NPs can accumulate in ocular tissues.

Human albumin-coated NPs (dry diameter, 21  ±  3  nm;

, 43  ±  5  nm) delivered via suprachoroidal injection

in rats were detected histologically in the posterior

eye after 6 weeks and by MRI up to 30 weeks post-in-

jection, without observable alterations in the retina

structure or functions [68]. Application of external

magnetic field to the damaged cornea after magnetic

NP administration improved transplantation of cul-

tured human corneal endothelial cells [64].

Functionalization of the magnetic particle surface

with various polymers (PEG, chitosan, polymethacryl-

ic acid, polylactic-co-glycolic acid, polyvinyl alcohol,

etc.) can enhance colloidal stability and biocompat-

ibility, reduce toxicity, and increase binding capac-

ity for cargo molecules [63, 66, 69]. Using external

magnetic field, magnetic NPs can be concentrated in

specific ocular regions (e.g., the retina) for targeted

drug delivery, minimizing off-target tissue exposure.

Magnetic field can also induce controlled NP degra-

dation and drug release [67].

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The potential of dual magnetite NP formula-

tions for ocular drug delivery has been demonstrat-

ed. Silica-coated NPs (D

, 141  ±  64  nm; ζ-potential,

−29.7  ±  9.5  mV) and Zonyl™ FSA-coated NPs (D

169  ±  63  nm; ζ-potential, +33.0  ±  8.03  mV) delivered

via topical drops in two-month-old mice reached the

photoreceptor layer and elicited significant biolog-

ical effects [66]. Sodium alginate-coated Fe

NPs

(60.29  ±  5.27  nm by SEM; D

, 399.1  nm; ζ-potential,

−24.4  ±  2.7  mV) applied to the periocular space and

exposed to a 0.6  T magnetic field, accumulated on the

human sclera, enhancing sodium diclofenac penetra-

tion 1.7-fold [70]. Starch-coated maghemite NPs (D

296  nm; ζ-potential, −24  mV) crossed the porcine sclera

at ~5  ng/mm

over 24  h under a 20  T/m field [71].

Functionalization of magnetite NPs with vascu-

lar endothelial growth factor (VEGF), which facilitates

transcytosis from the RPE to deeper ocular layers, en-

abled effective NP targeting to the choroid [72]. The

obtained NPs (D

, 128.6  nm; ζ-potential, −34.7  mV) in-

jected intravitreally in zebrafish embryos crossed the

RPE, while unmodified NPs remained in the RPE[72].

Targeting the retina with silica-coated iron oxide

(III)-based magnetic particles containing dexametha-

sone was studied in isolated bovine eyes and in  vivo

in rabbits [67]. NPs (∼200nm by TEM; D

, ∼  300 nm;

ζ-potential, not specified) delivered via intravitreal in-

jection were manipulated by a 30  mT magnetic field

and localized on the retina in bovine eyes and by

a 300  mT field in rabbits, reflecting higher vitreous

viscosity in rabbits [67].

CERIA NANOPARTICLES

Cerium oxide is a non-stoichiometric compound

(CeO

2-x

) due to the coexistence of two oxidation

states, Ce

and Ce

  [73]. This allows ceria NPs to re-

versibly absorb and release oxygen via the Ce

/Ce

redox cycle  [73]. The antibacterial activity of ceria

NPs arises not only from physical disruption of bac-

terial cells and ROS induction in acidic environments,

but also from the interaction of cerium ions with

thiol (-SH) groups of membrane-bound enzymes, as

well as downregulation of signaling pathway genes

and genes encoding efflux pumps. Additionally, ceria

NPs with well-defined facets can mimic phosphatase

enzymes, cleaving ATP and extracellular DNA mole-

cules [74]. To improve biocompatibility and prevent

aggregation, ceria NPs are functionalized with natural

or synthetic polymers, such as PEG, hyaluronic acid,

dextran, chitosan, polyacrylate, and polyvinylpyrroli-

done, or with low-molecular-weight carboxylic acids

(most frequently, citric acid) [73, 75, 76].

Comparative studies of ceria NPs biodistribution

in rats revealed that subcutaneous administration

(1  mg/kg) resulted in a higher cerium accumulation in

ocular tissues than intravenous injection (10  mg/kg),

with the greatest concentrations observed in the con-

junctiva and sclera, followed by diffusion into the

lens and aqueous humor [77]. Confocal microscopy

demonstrated that after intravitreal injection, ceria

NPs localized to the subretinal space of the retina[73].

Asingle intravitreal dose of up to 10mM (1.72  mg/eye)

caused neither histological changes in the retina nor

damage to photoreceptors or alterations in the ex-

pression of photoreceptor-specific genes (rhodopsin,

M- and S-opsins). The observed increases in proin-

flammatory cytokines were consistent with the levels

seen in saline-injected controls, indicating they were

due to the injection trauma rather than NP toxic-

ity [78]. In human lens epithelial cells, ceria NPs

(4  nm; ζ-potential, +44  mV) caused no elevation in

ROS levels at concentrations up to 200  µg/mL, where-

as 400µg/mL induced a 1.3-fold increase in ROS[79].

The NPs localized to the mitochondria, disrupted the

mitochondrial membrane potential and triggered ear-

ly apoptosis, including double-strand DNA breaks and

caspase activation. These findings indicate that the

toxicity of high-dose ceria NPs is primarily mediated

through the mitochondrial apoptotic pathway via ROS

overproduction and DNA damage [79].

On the other hand, low doses of ceria NPs can

reduce ROS levels. For example, ceria NPs (3-5  nm;

ζ-potential, +27  mV) at 10-500  µM were used to mit-

igate hydroxychloroquine-induced toxicity in human

RPE cells. When used simultaneously with 250  µM hy-

droxychloroquine, NPs showed no effects, with cell

survival being 52% and 33% at 24 and 48  h, while

pretreatment with the same NPs for 24  h prior to the

hydroxychloroquine exposure increased cell viability

to 68% and 52%, respectively [80].

The antioxidant properties of ceria NPs make

them promising agents for treating oxidative stress-re-

lated ocular diseases, including diabetic cataracts

[77], AMD [81, 82], dry eye syndrome [83, 84], and

chemical eye burns [75]. For example, intravitreal

administration of 1  mM ceria NPs (11.8  nm by TEM;

ζ-potential, not specified) in a rat model of acute

light-induced retinal damage (an analog of AMD) re-

duced neovascularization and suppressed VEGF ex-

pression and choroidal sprouting into the photorecep-

tor layer[81]. Similarly, treatment of human RPE cells

with 0.1  mM ceria NPs protected them from oxida-

tive stress and hypertrophy induced by 500  µM  H

While H

treatment significantly increased the ac-

tivity of superoxide dismutase  2 (SOD2), glutathione

peroxidase, and glutathione S-transferase, treatment

with ceria NPs restored these antioxidant markers

to near-normal levels. Fluorescein-labeled ceria NPs

persisted in the cytoplasm of RPE cells for up to two

months post-treatment [81].

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

Ophthalmic drug delivery often requires func-

tionalization of ceria NPs to enhance their therapeu-

tic efficacy [75, 83, 85]. For example, PEGylated ceria

NPs carrying the immunosuppressant cyclosporine

A were developed for the treatment of dry eye syn-

drome. These NPs (32.9  nm; ζ-potential, +17.8  mV) ef-

fectively suppressed ROS production in H

-stressed

human corneal epithelial cells in  vitro[83]. Treatment

with these NPs reduced the expression of stress-re-

lated genes while increasing the expression of genes

encoding mitochondrial proteins, such as thioredox-

in-interacting protein and mitochondrial outer mem-

brane translocase, suggesting potential protection

against oxidative epithelial dysfunction. In a mouse

model of induced dry eye syndrome, twice-daily top-

ical treatment with 0.096  mM cyclosporine  A in 1  mM

ceria NPs for three days reduced corneal inflamma-

tion, restored physiological structure, and normalized

the numbers of goblet cells (producers of the tear

film mucous layer) in the conjunctiva [83]. Overall,

cyclosporine-loaded ceria NPs modulated inflamma-

tory response and oxidative stress, promoted eyeball

regeneration, regulated immune–epithelial interac-

tions, and limited expression of fibrosis-related pro-

teins [83].

Ceria NPs have also been used to deliver multiple

synergistic therapeutic agents. For example, acetyl-

choline chloride and SB431542 (TGF-β receptor inhib-

itor) were co-encapsulated in poly(L-histidine)-coated

ceria NPs to enhance wound healing and suppress

scarring  [75]. These NPs (D

, 75  nm; ζ-potential,

not specified) were characterized by a high surface

roughness; coating them with poly(L-histidine) led to

a 24-fold increase in penetration into rabbit corneal

keratocytes. Drug release was prolonged and pH-de-

pendent, with <20% released at pH  7.4 and 65-95%

released at pH  6.0 over 96  h. Treatment with these

NPs in a rat model of alkaline corneal burn restored

corneal transparency and vasculature-free morpholo-

gy, achieving a 19-fold greater reduction in burn area

than the widely used drug dexamethasone [75].

Pilocarpine-loaded ceria NPs functionalized with

chitosan and adenosine A2A receptor antagonist

ZM241385 demonstrated a 250-fold increase in pi-

locarpine retention in the rabbit ciliary body com-

pared to pilocarpine solution[85]. In an experimental

glaucoma model, rabbits received single instillations

of pilocarpine in solution, in unmodified ceria NPs

[~70  nm by TEM and DLS (dynamic light scattering);

ζ-potential, +36  mV], or in ceria NPs functionalized

with chitosan and ZM241385 (~70  nm by TEM and

DLS; ζ-potential, +12.5  mV). While untreated rabbits

showed an intraocular pressure (IOP) of 29.3  mm  Hg,

the IOP in animals treated with pilocarpine solution

or unmodified NPs increased to 22.3  mm  Hg, then

temporarily decreased to normal levels after 4  h, and

rebounded to ~26  mm  Hg (i.e., the level of progres-

sive glaucoma) by day seven[85]. In contrast, pilocar-

pine-loaded functionalized ceria NPs achieved a sus-

tained IOP reduction to the normal values over seven

days. Histological analysis revealed that, despite the

apoptosis of retinal ganglion cells in all groups, pi-

locarpine-loaded functionalized ceria NPs reduced

retinal cell loss by 22.6% compared to pilocarpine

solution or non-functionalized NPs [85].

MESOPOROUS SILICA NANOPARTICLES

Mesoporous silica (SiO

) NPs have been developed

primarily to accommodate high-molecular-weight

compounds that cannot penetrate the micropores of

conventional zeolites. These NPs exhibit a large spe-

cific surface area, chemical stability, and biocompati-

bility and are considered relatively safe due to their

low toxicity [86]. Although SiO

NPs display weak

antibacterial activity attributable to electrostatic in-

teractions and local mechanical disruption of mem-

brane integrity, their primary role is to act as carriers

for targeted delivery of active compounds. The most

efficient drug delivery carriers are nanoparticles up

to 100  nm in size with neutral surface charge, with

rod-shaped particles often outperforming spherical

ones. Pore size is a critical parameter that influenc-

es both drug loading efficiency and release kinetics.

The physicochemical properties of SiO

NPs can be

precisely tuned during synthesis by adjusting the con-

centration of precursors and the presence of surfac-

tants [86].

The cytotoxicity of SiO

NPs has been investi-

gated both in  vitro in cultured corneal and retinal

cells [87-89] and in  vivo following instillation or in-

travitreal injection into rat eyes [87, 88]. Mesoporous

SiO

NPs (D

, 86  nm; ζ-potential, −32.17  mV) showed

no significant cytotoxicity toward corneal epithelial

cells at concentrations up to 100  µg/mL  [87]. Reti-

nal cells, however, were more sensitive to SiO

NPs,

which was manifested as increased ROS generation,

apoptosis, and cell cycle arrest, leading to the reti-

nal cell death. Moreover, the smaller the particle size

(from 50 to 7.5  nm) and the higher the administered

concentration (20-150  µg/mL), the greater the number

of retinal cells that died [88, 89]. Particles of 15  nm

in size were found in mitochondria, resulting in mi-

tochondrial dysfunction. These particles also caused

inflammation and apoptosis in retinal cells upon in-

travitreal administration in rats [88]. The number of

corneal cells producing interleukin  1β and tumor ne-

crosis factor  α increased 8 and 23 times on days 1

and 7, respectively, after SiO

NPs injection [88].

Local instillation of SiO

NP suspension (D

, 86  nm;

ζ-potential, −32  mV; 100  µg/mL) induced dry eye-like

INORGANIC NANOPARTICLES IN OPHTHALMOLOGY 1295

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

symptoms in rats [87]. Studies using rhodamine  B- or

FITC-labeled SiO

NPs showed that 7-nm particles ac-

cumulated in the corneal epithelium of isolated pig

eyes but did not penetrate into deeper layers within

24  h  [90].

Functionalization of SiO

NPs can mitigate their

cytotoxicity. For example, PEGylated SiO

NPs caused

no changes in the retina over both short- (7 days)

and long-term (4 weeks) observation [91], while

low-density lipoprotein-coated NPs were non-toxic to

human subconjunctival fibroblasts at concentrations

up to 1 mg/mL [92].

Surface modifications of SiO

NPs can improve

their interactions with the negatively charged oc-

ular surface and enhance the efficacy of released

drugs. Thus, SiO

NPs were functionalized with car-

boxymethyl chitosan [93], 3-aminopropyltriethoxysi-

lane [94], and other substances. For instance, SiO

NPs (80 nm; pore size, 2.8  nm) were engineered to

carry the mitochondrial-derived peptide humanin to

suppress retinal neovascularization in retinopathy;

these NPs were able to change the surface charge

upon exposure to ROS [91]. The surface of these NPs

was modified with acetyl-L-arginine that conferred a

positive charge (+2  mV), and thioketal-methoxy poly-

ethylene glycol, which served as a ROS trap. Under

oxidative stress, the charge of these NPs changed to

negative (−20  mV), which facilitated ocular diffusion.

In  vitro experiments confirmed the uptake of the syn-

thesized NPs by retinal epithelial cells, and in  vivo

experiments demonstrated their ability to completely

suppress retinal neovascularization in a mouse reti-

nopathy model [91].

In another approach to reducing neovascular-

ization, PEGylated SiO

NPs were used to co-deliver

the high-molecular-weight VEGF protein inhibitor

conbercept (143  kDa) and the low-molecular-weight

anti-inflammatory factor MCC950 (426  Da) [95]. The

resulting NPs (280  nm; ζ-potential, −12.3  mV) were

non-cytotoxic and were 3-5 times more efficient at

suppressing endothelial angiogenesis and inflamma-

tion in  vitro than free drugs. A single intraocular

injection suppressed VEGF and key proinflammatory

cytokines (e.g., IL-6) at the mRNA and protein levels,

as well as mitigated diabetes-induced retinal vascu-

lar dysfunction, choroidal neovascularization, and

inflammatory reactions by inhibiting the expression

of inflammatory and angiogenic factors in diabetic

mouse models for up to 6 months [95].

SiO

NPs have shown a significant potential for

the delivery of antitumor and therapeutic agents.

For instance, mitomycin  C loaded into SiO

NPs (D

280  nm; ζ-potential, not specified) conjugated with

low-density lipoprotein demonstrated a positive

therapeutic effect in the treatment of benign fibro-

vascular tissue overgrowth on the conjunctiva (pte-

rygium) [92]. Incorporation of mitomycin  C into NPs

doubled its antiproliferative activity against pteryg-

ium fibroblasts compared to the free drug, with no

effect observed on normal fibroblasts [92]. Similarly,

5-fluorouracil encapsulated in SiO₂ NPs coated with

carboxymethyl chitosan (D

, 249  nm; ζ-potential,

−5.72  ±  4.04  mV) increased the drug’s half-life in the

aqueous humor from 3  h (free drug) to 7.6  h when

delivered as an NP suspension in rabbit eyes [93].

This formulation also doubled both the time to reach

the maximum concentration (from 2 to 4  h) and the

peak concentration itself (from 15.6 to 30.8  µg/mL per

hour) [93].

Hybrid SiO

–chitosan NPs have been used to de-

liver poorly water-soluble antifungal drug terconazole

[96]. These NPs (610-770  nm; ζ-potential, +39  mV) ex-

hibited strong in  vitro affinity for mucins. Encapsu-

lation of terconazole substantially altered drug phar-

macokinetics in rabbit tear fluid: the maximum drug

concentration increased 4.6-fold; the time to reach

this concentration extended from 1 to 7  h; and the

area under the time–concentration curve (AUC) rose

nearly 20-fold [96].

Mesoporous SiO

NPs functionalized with 3-ami-

nopropyltriethoxysilane were also employed to de-

liver the immunosuppressant tacrolimus (225  nm;

ζ-potential, +33  mV). Intravitreal administration in

rat eyes induced no retinal abnormalities, vitreous

hemorrhage, neovascularization, retinal detachment,

or optic nerve atrophy, indicating safety of these NPs

and potential for ocular therapies [94].

Another promising strategy involves incorporat-

ing drug-loaded SiO

NPs into hydrogel contact lens-

es [97,98]. Lenses retained optical transparency after

inclusion of NPs with a size of 65-110  nm [97, 98].

NPs modified with 3-aminopropyltrimethoxysilane en-

hanced the release of hyaluronic acid compared to

lenses without NPs [98]. Encapsulation of the IOP-re-

ducing drug brimonidine in NP-loaded lenses extend-

ed its retention in rabbit tear fluid to 96  h, compared

with 24  h in lenses without NPs and only 1  h for the

drug solution [97].

CALCIUM SALT NANOPARTICLES

Calcium carbonate (CaCO

) is one of the most

common inorganic materials with a wide range of ap-

plications in biomedicine, particularly as a platform

for delivering biologically active substances. The ad-

vantages of CaCO

-based materials include low cost,

lack of toxicity, and particle biodegradability [99].

CaCO

exists in three polymorphic modifications: cal-

cite, aragonite, and vaterite. Among them, vaterite is

particularly attractive as a carrier due to its porous

structure and highly developed surface [99].

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

CaCO

particles are typically obtained by mixing

the sources of calcium cations and carbonate anions.

Without additives, the resulting particles are usually

micron-sized [100, 101]. Submicron CaCO

can be ob-

tained by introducing agents, such as glycerol [102],

ethylene glycol [103], or surfactants (e.g., Tween 20,

Triton X-100, sodium dodecyl sulfate, etc.) [104] into

the reaction medium. For example, ethylene glycol

enables the formation of CaCO

NPs 200 nm in size

[103, 104].

CaCO

NPs can exhibit antibacterial activity due

to their solubility in acidic environments and calci-

um ion release, which alters local pH and inhibits

bacterial carbohydrate metabolism. However, the

mechanism of action of these NPs likely involves ad-

ditional factors, as 250 µg/mL CaCO

NPs completely

suppressed S. aureus growth within 16 h, whereas

5  mg/mL conventional CaCO

showed no effect [105].

Although the studies on the cytotoxicity of CaCO

NPs

and microparticles in ocular tissues are lacking, indi-

rect evidence from other types of cells suggests low

toxicity. For example, treatment of human embryonic

kidney cells with CaCO

-based particles at a concen-

tration of 250-1000 µg/mL did not lead to cytotoxic

effects [102, 106].

Currently, the use of CaCO₃ NPs in ophthalmol-

ogy has not been reported. Nevertheless, it can be

argued that vaterite NPs are promising as carriers of

ophthalmic drugs, since vaterite has an affinity for

mucin, the primary component of the tear film cov-

ering the eye surface [100, 107]. Furthermore, instil-

lation of vaterite microparticles (3-4 µm, 10  mg/mL)

into rabbit eyes caused no irritation and has been

proposed as a method for delivering superoxide dis-

mutase 1 (SOD1) to prolong its activity [100].

Calcium phosphate nanoparticles (NPs), partic-

ularly in the form of hydroxyapatite, also offer a

broad potential for ophthalmic applications. Being a

natural component of the human body, calcium phos-

phate is inherently biocompatible and biodegradable

[108]. The antibacterial mechanism of calcium phos-

phate NPs is complex. Although Ca

ions exhibit low

direct toxicity, they modulate membrane permeabili-

ty, facilitating NP penetration into cells. At the phase

boundary, NPs generate a “comet-like tail” of atomic

clusters, which irreversibly bind to bacterial pepti-

doglycan upon contact, leading to bacterial cell wall

destruction [109].

At a concentration of 1  mg/mL, calcium phos-

phate particles showed negligible hemolysis of rab-

bit erythrocytes [110]. Cytotoxicity studies in mouse

preosteoblasts revealed that low-crystallinity of hy-

droxyapatite NPs and NP agglomeration increased

their toxicity. NPs localized to lysosomes, where they

gradually dissolved, thus elevating intracellular cal-

cium levels (a key signal for cell death) and poten-

tially raising ROS levels [111]. In general, smaller

NPs (170-220 nm) were associated with higher intra-

cellular calcium levels and ROS production, whereas

larger agglomerates (2-5 µm) induced only modest

increases in calcium and ROS but drastically reduced

metabolic activity (up to 15-fold) after 72 h of expo-

sure [111].

Calcium phosphate-based NPs are primarily syn-

thesized via precipitation from solutions [112-119], in-

cluding in the presence of phosphatases [120, 121]. By

adjusting parameters such as reagent concentration,

pH, and temperature, particles with specific size, sur-

face charge, morphology, and phase composition can

be obtained [116, 118, 120, 122].

A distinctive feature of calcium phosphate-based

NPs is their versatility as carriers of both low- and

high-molecular-weight compounds [108, 112, 122,

123]. Drugs can be incorporated into NPs through

interactions between calcium ions and functional

groups of drug molecules, such as phosphate groups

in DNA/RNA [119, 124, 125] or carboxyl groups in

small molecules and proteins [115, 117, 118]. Depend-

ing on the compound’s properties, drug loading can

occur during NPs synthesis or via adsorption onto

preformed NPs. For example, the use of co-precipita-

tion allowed to achieve high loading efficiencies (35-

40%) for the ACE inhibitors lisinopril and enalapril,

as well as for SOD1, compared to adsorption (17% for

lisinopril) [110, 116, 118].

Calcium phosphate NPs (D

, 340 nm; ζ-potential,

−17  mV) coated with the disaccharide cellobiose with

the included ACE inhibitor lisinopril [116] or the β-ad-

renergic blocker timolol [123] were successfully used

to reduce IOP in rabbits. These formulations produced

a 1.5-2-fold greater IOP reduction compared to aque-

ous solution of the corresponding drugs. Similarly,

calcium phosphate NPs (D

, 460  ±  30 nm; ζ-potential,

−4  ±  2  mV) loaded with SOD1 demonstrated potential

for treating immune uveitis [115, 122]. Incorporation

of SOD1 into NPs led to a more pronounced suppres-

sion of uveitis symptoms, including a 20% reduction

in eyelid edema and hyperemia and a 40% decrease

in fibrin clots in the anterior chamber [122].

Coating calcium phosphate NPs with chitosan

[117, 118, 126] increased the NP affinity to the eye

surface, which contains negatively charged mucins.

Variants used included chitosan with an average mo-

lecular weight of 89kDa [126], chitosan with an aver-

age molecular weight of 5kDa, and 72-kDa glycol-chi-

tosan [117, 118]. Chitosan-coated NPs loaded with

timolol (89-kDa chitosan; D

, 140  ±  80 nm; ζ-poten-

tial, +16  ±  4  mV) or ACE inhibitors lisinopril (89 kDa

chitosan; D

, 130  ±  80 nm; ζ-potential, +17  ±  4  mV)

and enalapril (5-kDa chitosan; D

, 180  ±  30 nm, ζ-po-

tential, +7  ±  3  mV and 72 kDa glycol-chitosan; D

280  ±  30 nm; ζ-potential, +16  ±  3  mV) nearly doubled

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

enalapril retention in the rabbit tear fluid and sig-

nificantly enhanced the IOP-lowering effect compared

to free drugs or uncoated NPs [117, 118, 126]. Drug

loading efficiency was highest in the hybrid particles:

40  ±  10% for enalapril in bare calcium phosphate NPs

, 110  ±  20nm; ζ-potential, −37  ±  2  mV), 66  ±  5% in

5-kDa chitosan-coated NPs, and 72  ±  8% in glycol-chi-

tosan-coated NPs [110]. Chitosan coatings also slowed

drug release nearly twofold [118].

Besides the possibility of loading with low- and

high-molecular-weight compounds, another advantage

of calcium phosphate NPs is the capacity for simulta-

neous incorporation of multiple drugs. For example,

NPs coated with a 5-kDa chitosan (D

, 140  ±  20 nm;

ζ-potential, +20  ±  1  mV) successfully carried both

enalapril (348Da) and SOD1 (32.5kDa) [117]. Co-load-

ing did not significantly alter the drug release: SOD1

was fully released within 2 h, while 50% of enalapril

was released during the same period.

In vivo experiments demonstrated a synergistic

effect of jointly included drugs: 1 h after instillation,

the combined IOP reduction was 3.5 mm Hg, exceed-

ing the theoretical sum of individual effects (1.4 mm

Hg for SOD1 + 0.8 mm Hg for enalapril = 2.2 mm

Hg), despite a lower enzyme content in the co-loaded

NPs [117].

In summary, calcium phosphate NPs are promis-

ing ophthalmic drug carriers due to their low toxicity,

ease of synthesis, capacity to encapsulate both low-

and high-molecular-weight compounds, and ability to

enhance their therapeutic efficacy.

Table1 summarizes the key characteristics of the

main types of inorganic nanoparticles discussed in

this review. Currently, no FDA-approved ophthalmic

treatments directly utilize inorganic nanoparticles.

However, safety data exist for macroform applica-

tions:

• Silica is approved by the Food and Drug Admin-

istration (FDA) as a component of intravitreal

implants (ILUVIEN, NDA: N201923; YUTIQ, NDA:

N210331).

• Calcium phosphate is approved for use in orbital

implants composed of porous hydroxyapatite

(Bio-Eye®, PMA: P890041).

• Zinc oxide is approved as a key component

in the therapy for AMD (AREDS/AREDS2;

ClinicalTrials.gov: NCT00000145).

Nanoparticle formulations are undergoing clinical

trials in related fields:

• Gold nanoparticles (CNM-Au8) have successfully

completed Phase  II trials for the treatment of

multiple sclerosis (NCT03993171)[127] and amyo-

trophic lateral sclerosis (NCT04098406) [128] and

are currently in Phase  III trials (NCT04297683).

• Silica nanoparticles are in Phase  II trials

(NCT01266096)[129] for precision tumor imaging

and Phase  I trials (NCT03465618) for PET-based

brain imaging.

CONCLUSION

New drug carriers developed for the use in

ophthalmology offer high stability and prolonged

drug release, enhance interaction with the ocular

surface, increase drug residence time, and improve

its penetration into eye tissues, ultimately extend-

ing the duration of therapeutic action. This allows

for lower drug doses and reduced administration

frequency, while also minimizing local and system-

ic side effects. Ex  vivo and in  vivo studies in var-

ious animal models have demonstrated benefits

such as reduced IOP, decreased oxidative stress,

inhibition of neovascularization, and preservation

Table 1. Main types of inorganic nanoparticles for ophthalmology applications

NP type Advantages Risks Potential applications

Au • chemical stability

and inertness;

• biocompatibility;

• ability to penetrate the BRB;

• surface plasmon resonance

effect;

• antiangiogenic activity;

• antioxidant activity;

• anti-inflammatory properties

• bioaccumulation;

• potential transport

of toxins through

the BRB;

• photothermal tissue

damage;

• oxidative stress;

• phototoxicity

• biosensors;

• photothermal therapy;

• diagnostic imaging (OCT

and photoacoustic imaging);

• contact lens doping;

• anti-VEGF therapy;

• delivery of drugs, DNA,

and RNA

Ag • antibacterial activity;

• surface plasmon resonance

effect;

• antiangiogenic activity;

• anti-inflammatory properties

• bioaccumulation;

• argyrosis;

• cytotoxicity;

• genotoxicity;

• neurotoxicity

• treatment of bacterial

conjunctivitis and keratitis;

• diagnostics (biosensors);

• anti-VEGF therapy

POPOVA et al.1298

BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

Table 1 (cont.)

NP type Advantages Risks Potential applications

TiO

• chemical stability;

• photocatalytic antibacterial

effect;

• UV protection;

• high sorption capacity

• bioaccumulation;

• cornea and lens

transparency impairment;

• phototoxicity;

• neurotoxicity;

• inflammatory response

• treatment of bacterial

conjunctivitis and keratitis;

• photodynamic and

photocatalytic therapy;

• contact lens doping

ZnO • antibacterial activity;

• antifungal effect;

• UV protection;

• selective toxicity

to cancer cells;

• biocompatibility;

• biodegradation

in the body;

• high sorption capacity

• phototoxicity;

• lysosomal membrane

rupture;

• ionic toxicity;

• inflammatory response;

• systemic absorption

• treatment of bacterial

conjunctivitis and keratitis;

• treatment of fungal

infections;

• acceleration of corneal wound

epithelialization after burns

or surgeries;

• drug delivery (potentially)

α-Fe

γ-Fe

• magnetic properties;

• biocompatibility;

• biodegradation

• thermal burn;

• local accumulation;

• magnetic aggregation;

• siderosis;

• cytotoxicity

• controlled drug delivery

and release;

• delivery to the posterior

segment of the eye;

• MRI imaging;

• magnetic hyperthermia

of tumors

CeO

2-x

• antioxidant properties;

• neuroprotective

properties;

• regeneration of antioxidant

activity;

• antiangiogenic activity;

• anti-inflammatory

properties

• cytotoxicity;

• phosphatase activity;

• bioaccumulation

• antioxidant agent;

• protection of retinal cells;

• anti-VEGF therapy;

• drug delivery (potentially)

SiO

• porosity and very high

sorption capacity;

• chemical stability;

• biocompatibility;

• biodegradation

• abrasiveness;

• aggregation in tear fluid;

• local accumulation;

• cytotoxicity

• prolonged delivery of low-

and high-molecular-weight

substances

CaCO

• porosity and very high

sorption capacity;

• mucoadhesiveness;

• pH-dependent release;

• biocompatibility;

• biodegradation;

• high affinity for DNA/RNA

• abrasiveness;

• aggregation in tear

fluid;

• phase transition (abrupt

drug release);

• homeostasis disruption

(excess Ca

ions);

• local alkalization;

• tissue calcification

• prolonged delivery of low-

and high-molecular-weight

substances;

• delivery and protection

of DNA and RNA

Ca phosphate • porosity (high sorption

capacity);

• pH-dependent release;

• biocompatibility;

• biodegradation;

• structural stability;

• high affinity for DNA/RNA

• aggregation in tear fluid;

• homeostasis disruption

(excess Ca

and PO

3−

ions);

• tissue calcification

• prolonged delivery

of low- and high-molecular-

weight substances;

• delivery and protection

of DNA and RNA

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 8 2026

of cell morphology across different disease models,

highlighting the therapeutic potential of NP-based

systems.

Among different carriers, inorganic NPs are par-

ticularly promising for ophthalmic application. Their

main advantages are low production costs and con-

trolled physical properties. The large specific surface

area of NPs enables efficient loading of both low- and

high-molecular-weight therapeutics, while their inor-

ganic composition provides wide opportunities for

multimodal therapy and diagnostics. Inorganic NPs

present opportunities to significantly advance oph-

thalmic diagnostics and treatment.

Common challenges in using inorganic NPs in-

clude the complex anatomy of the eye, the presence

of multiple physiological barriers, the need for sta-

ble and sterile formulations, and limited data on the

long-term biocompatibility and metabolism of carri-

ers in ocular tissues. Addressing these issues is es-

sential for successful clinical translation of NP-based

ocular drug delivery systems.

AuNPs and certain metal oxides can be used in

diagnostics as imaging contrast agents. Their ability

to accumulate in tumors suggests their application

in the therapy of oncological diseases. AgNPs have a

great potential in ophthalmology due to their potent

antimicrobial properties. However, the potential tox-

icity of these particles can limit their clinical use. In

contrast, silica NPs and insoluble calcium salts are

minimally toxic and possess a porous structure for

versatile drug loading. Due to their biodegradability

and biocompatibility, NPs based on silica and calci-

um salts appear to be the safest and most promising

agents for the local delivery of drugs intended for the

treatment of eye diseases.

Abbreviations

ACE angiotensin-converting enzyme

AMD age-related macular degeneration

hydrodynamic diameter

IOP intraocular pressure

NP nanoparticle

ROS reactive oxygen species

RPE retinal pigment epithelium

SOD superoxide dismutase

TEM transmission electron microscopy

VEGF vascular endothelial growth factor

ζ-potential electrokinetic potential

Contributions

E.V.P. and V.E.T. wrote the text of the article; O.A.K.

developed the concept, supervised the study, and ed-

ited the manuscript.

Funding

This study was supported by the State Assignment

to Lomonosov Moscow State University (registration

number 121041500039-8).

Ethics approval and consent to participate

This work does not contain studies involving human

or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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