Ocular Nanomedicine

Abstract

Intrinsic shortcomings associated with conventional therapeutic strategies often compromise treatment efficacy in clinical ophthalmology, prompting the rapid development of versatile alternatives for satisfactory diagnostics and therapeutics. Given advances in material science, nanochemistry, and nanobiotechnology, a broad spectrum of functional nanosystems has been explored to satisfy the extensive requirements of ophthalmologic applications. In the present review, the recent progress in nanosystems, both conventional and emerging nanomaterials in ophthalmology from state-of-the-art studies, are comprehensively examined and the role of their fundamental physicochemical properties in bioavailability, tissue penetration, biodistribution, and elimination after interacting with the ophthalmologic microenvironment emphasized. Furthermore, along with the development of surface engineering of nanomaterials, emerging theranostic methodologies are promoted as potential alternatives for multipurpose ocular applications, such as emerging biomimetic ophthalmology (e.g., smart electrochemical eye), thus provoking a holistic review of "ocular nanomedicine." By affording insight into challenges encountered by ocular nanomedicine and further highlighting the direction of future studies, this review provides an incentive for enriching ocular nanomedicine-based fundamental research and future clinical translation.

Keywords: diagnostics; nanomedicine; ocular; ophthalmology; therapeutics.

Figure 1

Schematic illustration of ocular nanomedicine for versatile biomedical applications in opthalmology.

Figure 2

The active targeting capability of liposomal nanoparticles. a,b) A schematic illustration of functionalized fluorescent dipalmitoylphosphatidylcholine‐cholesterol liposomes by coupling with monoclonal antibody against intercellular adhesion molecule 1 (ICAM‐1) to target the ICAM‐1 on the activated endothelial surface. c) Intravascular flow of tumor necrosis factor (TNF) for 6 h caused endothelial expression of ICAM‐1. Scale bar, 100 µm. d,e) Anti‐ICAM‐1 nanocarriers binded to the TNF‐treated endothelial surface. Scale bars, 100 µm in (d) and 25 µm in (e). f) Non‐TNF‐activated blood vessels presented minimal liposome integration. Scale bar, 100 µm. g,h) IgG‐coupled liposomes did not adhere to the blood vessels. Scale bar, 100 µm. i) Local inflammation was induced by directly injecting lipopolysaccharide‐soaked microbeads into vascularized hydrogel via opening of the culture chamber. j) The vascularized hydrogel after incubation of lipopolysaccharide (LPS)‐laden microbeads clearly showed the spatially graded activation of ICAM‐1. k) The expression level of ICAM‐1 was the highest in the vicinity of LPS‐microbeads and decreased gradually with increasing distance from the source of inflammation. The expressed level was inversely proportional to the distance from the lipopolysaccharide microbeads. Scale bar, 100 µm. l,m) Adhering to anti‐ICAM‐1 nanoparticles perfused by vasculature corresponds to the spatial pattern of ICAM‐1 stimulation, further revealing the active targeting ability of functionalized liposomal nanoparticles. Scale bar, 100 µm. Adapted with permission.^{[ 18a ]} Copyright 2019, American Chemical Society.

Figure 3

Formulation and application of flurbiprofen sodium (FBP)‐encapsulated nanomicelles. a) 1, 2‐distearoyl‐sn‐glycero‐3‐phosphoethano–lamine‐N‐[maleimide (polyethylene glycol)‐2000] (DSPE‐PEG₂₀₀₀‐MAL) and cyclic peptide ligand c (cRGD) peptide to fabricate DSPE‐PEG₂₀₀₀‐cRGD. b) Formulation of FBP‐loaded nanomicelles (M‐FBP) and cornea‐targeting peptide‐functionalized nanomicelles (CTFM‐FBP). c) Schematic illustration of nanomicelle‐facilitated targeted ocular delivery. Reproduced under the terms of the Creative Commons CC‐BY license.^{[ 28 ]} Copyright 2018, The Authors. Published by Wiley‐VCH.

Figure 4

Preparation and application of boronic acid‐rich dendrimer (BARD)‐mediated intracellular superoxide dismutase (SOD) delivery. a–c) Intravitreal injection of BARD/SOD nanoformulations for intracellular SOD delivery. a) The eyeball structure from outside to inside were enlarged, and presented from right to left. b) Binding curve and c) fractional saturation curve of BARD/SOD‐FITC nanoformulations at different polymer concentrations, and SOD‐FITC was fixed at 176 nm. n = 3, data presented as mean ± SD. d–h) Confocal microscope images of Brn3a (green), TUNEL (red), Hoechst (blue), and merged staining in the ganglion cell layer (GCL). d) Normal control rat; e) normal rat injected with SOD; f) normal rat injected with BARD/SOD nanoformulation; g) normal rat injected with BARD; h) ischemia/reperfusion rat. Scale bar: 20 µm. RGC, retinal ganglion cell; BC, bipolar cell; HC, horizontal cell; AC, amacrine cell. ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer. Reproduced with permission.^{[ 33 ]} Copyright 2020, Elsevier Ltd.

Figure 5

Preparation and application of DNA/poly(lactic‐co‐glycolic acid) (PLGA) hybrid hydrogel (HDNA). a) Schematic illustration showed the complexation of dexamethasone (DEX) with HDNA (HDEX)‐ and HDNA‐mediated sustained DEX release. b) Rabbits were topically treated with indicated materials and then were collected at 1/4, 1, 2, 4, 8, 10, and 24 h after treatment to detect the drug in tissue. c) Rabbits were topically treated with HDNA‐FluoSpheres or Fluo‐Spheres. FluoSpheres were entrapped in DNA hydrogel or PBS instead of PLGA nanoparticles. Representative fundus camera images of rabbits at 1/12, 1, 6, 10, and 16 h after instillation. Scale bars: 0.5 cm. Reproduced with permission.^{[ 4 ]} Copyright 2019, American Chemical Society.

Figure 6

Chitosan (CHI)‐based self‐assembly nanofilms for corneal wound repair. a) Schematic illustration of conventional layer‐by‐layer (LbL) and shear flow‐driven LbL (SF‐LbL) assembly processes. Polymer molecules mainly showed a random coil structure in static solution, but achieved a more stretched structure in flow state via coil‐stretch transition. b–d) Remodeling of acellular matrix of the porcine cornea and modification of a rat eye in situ by SF‐LbL‐assembled coating strategy. b) Schematic illustration of (CHI‐FITC/hyaluronic acid (HA))₁₅ film fabrication on a wounded porcine eye in situ. c) Bright‐field (top) and fluorescence (bottom) photos of an alkali‐burned rat eye covered with SF‐LbL‐assembled (CHI‐FITC/HA)₁₅ films. d) Fluorescence images of a repaired rat cornea in histologic section. Scale bars = 200 µm. Reproduced with permission.^{[ 45 ]} Copyright 2019, American Chemical Society.

Figure 7

Photoablation by light‐triggered vapor gold nanoparticles (AuNPs)‐based nanobubbles for human vitreous opacity therapy. a) Schematic illustration of the fate of HA‐coated AuNPs in vitreous. b) Schematic illustration of binding of AuNPs and HA to a vitreous opacity. c) Dark‐field microscopy of vitreous in an 88‐year‐old patient showed that the vision‐disturbing floaters were caused by the age‐related vitreous collagen aggregation into visible fibers in central vitreous body. Floaters could also be caused by the dense collagen matrix in outer vitreous body (arrow) after posterior vitreous detachment. d) Schematic illustration of the production of vapor nanobubbles after AuNPs illumination by a pulsed laser. e) Schematic illustration of the concept of “AuNPs‐assisted photoablation”: AuNPs bind to the opacities by intravitreal injection, and then local pulsed‐laser illuminates to generate vapor nanobubbles, which mechanically ablate the vitreous opacities. Reproduced with permission.^{[ 51 ]} Copyright 2019, American Chemical Society.

Figure 8

Vacancy‐induced antibacterial activity of two‐dimensional transition metal dichalcogenides (XS₂) quantum dots (QDs) against drug‐resistant bacteria. a) Schematic diagram of vacancy‐induced antibacterial activity of WS_2‐y (remaining sulfur vacancies and reducing sulfur content) QDs for bacterial keratitis treatment. Antibacterial mechanism of WS_2–y QDs. b) Schematic illustration of cellular metabolism. Intracellular and extracellular electrons transfer (IET and EET) produce an electron loop between intracellular and extracellular environment, and the respiratory proteins on microbial membrane work as an electron conduit. c) Disturbed cellular metabolism by WS_2–y QDs. WS_2–y limited the electronic transfer, disturbed cellular metabolism, and triggered microbe death. d) Schematic diagram of the WS₂ field‐effect‐transistor biosensor. e,f) Schematic circuitry to illustrate the proposed mechanism for different responses of bacteria to WS₂ and WS_2–y QDs, respectively. In contrast to Staphylococcus aureus solution, the current is little changed in WS₂ (S₀) QDs and S. aureus solution, suggesting a still balance of IET and EET processes. However, a significant current decreasing was observed in WS_2–y (S₁–S₅), demonstrating the current for the IET process is blocked. Thus, the bactericidal activity of WS_2–y stemmed from the blocked ET on the microbial membrane. Reproduced with permission.^{[ 57 ]} Copyright 2020, Wiley‐VCH.

Figure 9

Mesenchymal stem cell (MSC)‐derived exosomes and retinal ischemia‐reperfusion. a–d) Characterization of MSC‐nanovesicles (EVs). a) Nanoparticle tracking analysis histogram showed the size distribution of isolated MSC‐EVs, and indicating that the majority of MSC‐EVs are likely exosomes. b) Western blot demonstrating the characteristic surface markers of exosomes, CD63, CD9, CD81, and HSP70α, expressed in MSC‐EV preparations, but not in MSC‐conditioned medium (CM) depleted of EVs. c) TEM image of cup‐shaped MSC‐EVs (approximately 100 nm) isolated from MSCs, consistent with exosomal size. d) MSC‐EVs labeled with CD63 antibody to exosome surface markers by immunogold. e) Intravitreal injection of green fluorescent MSC‐EVs into normal and ischemic eyes by fundus imaging at day 1 and 3, weeks 1, 2, and 4. Fluorescent MSC‐EVs presented for up to 4 weeks. f) Graph showed the binding of fluorescently labeled MSC‐EVs to 50 µg of isolated vitreous. The binding of MSC‐EVs to the vitreous was saturable. Data presented as mean ± SD (n = 6). Reproduced with permission.^{[ 68 ]} Copyright 2019, Elsevier Ltd.

Figure 10

Schematic illustration of the fabrication and application of dual‐response nanocomposites in chemophotothermal therapy for choroidal melanoma, and the microenvironment‐triggered degradation of cross‐linked poly(nisopropylacrylamide) (PNIPAM) hydrogels. RENP, rare‐earth nanoparticles; ICG, indocyanine green; Dox, doxorubicin; FA, folic acid; HCM, human choroidal melanoma; GSH, glutathione; NIR, near‐infrared window; TME, tumor microenvironment. Reproduced with permission.^{[ 85 ]} Copyright 2020, American Chemical Society.

Figure 11

A biodegradable nanocapsule delivers a CRISPR‐Cas9 ribonucleoprotein (RNP) complex for in vivo genome editing. a) Sp.Cas9 showed a heterogeneous surface charge due to both negative and positive amino acids residues, as well as the negatively charged sgRNA. A schematic depiction for the formation of covalently crosslinked, yet intracellularly biodegradable, nanocapsule to deliver RNP complex by in situ free radical polymerization. b) A schematic illustration of the proposed mechanism of cellular uptake of nanocapsule and subcellular release of RNP. c) Schematic illustration of tdTomato locus within the Ai14 mouse strain. A STOP cassette including three SV40 polyA sequences prevented the transcription of downstream red fluorescent protein variant, tdTomato (left). When cells are edited by CRISPR/Cas9 to excise the STOP cassette via cut sites present in each of repeats, they will express tdTomato (right). d) Scheme of the targeted genome editors in retinal pigmented epithelium (RPE) cells by subretinal injection. e) Illustration of nanocapsule‐ATRA. f) The efficiency of genome editing as quantified by percent of area of whole RPE with genome editing reporter (tdTomato+). PBS (n = 3), RNP (n = 4), NC (n = 6), or NC‐ATRA (n = 6). Data presented as mean ± SD. g) Scheme of whole mount RPE preparation and representative photos of tdTomato+ signal (black) after subretinal injection for 12 days. Whole RPE layer is outlined. n = 3. Reproduced with permission.^{[ 94 ]} Copyright 2019, Nature Publishing Group.

Figure 12

Synthesis and anti‐inflammatory effects of curcumin (CUR)‐loaded gambogic acid (GA)–coupled‐PLGA (PLGA‐GA₂) nanoparticles (PLGA‐GA₂‐CUR). a) Schematic illustration of the synthesis of PLGA‐GA₂‐CUR. b) Characterization of PLGA‐GA₂‐CUR by the dynamic light scattering size distribution with an insert depicting model particle. c) Scanning electron microscope (SEM) image of PLGA‐GA₂‐CUR. d–f) Anti‐inflammatory effects of topical PLGA‐GA₂‐CUR on a canine model with acute intraocular inflammation. After intracameral administration of lens protein at t = 0 h, eyes were serially analyzed by the semiquantitative preclinical ocular toxicology scoring (SPOTS) system, including evaluation of d) aqueous flare, e) pupillary light reflex, and f) conjunctival swelling. In contrast to topical treatment with prednisolone acetate and untreated controls, there was a significance of topical PLA‐GA₂‐CUR injection as determined by a two‐way ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001. TFA, trifluoroacetic acid; TREN, tris(2‐aminoethyl)amine; DIEA, N,N‐diisopropylethylamine; EDC, 1‐ethyl‐3‐ (dimethylaminopropyl) carbodiimide. Reproduced with permission.^{[ 98 ]} Copyright 2020, AAAS.

Figure 13

Targeted delivery of self‐assembled poly (ethylene glycol)‐b‐poly(propylene sulfide) (PEG‐b‐PPS) micelles (MC) to Schlemm's canal endothelial cells for glaucoma treatment. a) Schematic illustration of peptide‐displaying micelles. b) The peptide‐targeting construct including PEG spacer, targeting peptide, and palmitoleic acid tail. c) LCMS spectra of the purified Flt4‐targeting peptide construct. d–f) Targeted delivery of latrunculin in mouse eyes. d) Illustrative overview of two different intraocular pressure (IOP) measurement schedules. Trials #1 and Trial #2 IOP timepoints presented with black and gray arrows, respectively. e) The Trial #1 consisted of 2 µL intracameral injection of black (BL)‐MC or tLatA MC (40 mg mL⁻¹, 5% peptide, 17 µM LatA). IOP was detected prior to injection, and after 24 and 48 h. f) In trial #2, 2 µL of BL‐MC, ntLatA‐MC, or tLatA‐MC (15.5 µM LatA, 40 mg mL⁻¹ 5% peptide) micelles were injected into one eye of 5 mice each. IOP was detected prior to injection and at three time points during a 48 h time course. Data presented as mean ± SEM (n = 5). Trial #1 and # 2 significance determined by unpaired t‐test and ANOVA with post hoc Tukey's multiple comparisons test (*p < 0.03), respectively. Reproduced with permission.^{[ 105 ]} Copyright 2020, Wiley‐VCH.

Figure 14

A distinctive hybrid system based on zeolitic imidazolate framework (ZIF) for synergistic photodynamic therapy and chemotherapy of endophthalmitis. a) Schematic illustration of constructed hybrid system ZIF‐8‐polyacrylic acid (ZIF‐8‐PAA)‐methylbenzene blue (MB)@silver nanoparticles (AgNPs)@vancomycin (Van)/NH‐PEG (ZPMAVP) for endophthalmitis treatment by synergistic chemotherapy and photodynamic therapy. b,c) Photographs and slit lamp micrographs of endophthalmitis resulted from Staphylococcus aureus (b) and methicillin‐resistant staphylococcus aureus (MRSA) (c) after treatment with three groups of PBS, Van, and ZPMAVP nanoparticles + laser (202 mW cm⁻²) at 1, 3, and 7 days, respectively. Reproduced with permission.^{[ 112 ]} Copyright 2019, Wiley‐VCH.

Figure 15

Auto‐regenerative antioxidant significantly attenuates choroidal neovascularization. a) Schematic illustration of glycol chitosan‐coated antioxidant ceria nanoparticles (GCCNP) synthesis. b) Photos of color changes of GCCNPs on addition of H₂O₂, reflecting auto‐regenerative nature of GCCNPs. c) Representative fundus (fluorescein angiography (FA) and BF) and optical coherence tomography (OCT) photographs (OCT‐BF and OCT‐color) before and 14 d following intravitreal injections of GCCNPs after laser induction. Red arrows represented the laser‐damaged areas. Reproduced with permission.^{[ 99b ]} Copyright 2017, American Chemical Society.

Figure 16

Biomimetic electrochemical eye (EC‐EYE) with hemispherical perovskite nanowire array retina. a,b) The overall comparison of human and EC‐EYE imaging systems. Schematic illustration of human visual system (a1), human eye (a2), and human retina (a3). Schematic illustration of EC‐EYE imaging system (b1), working mechanism of EC‐EYE (b2), and nanowire in hemispherical porous‐alumina‐membrane (PAM) template and molecular structure (b3). c–i) Detailed structure of EC‐EYE: c) Layered structure, d) side‐view, and e) top‐view of a completed EC‐EYE. f) Low‐resolution cross‐sectional SEM image of hemispherical PAM/nanowire. g) Cross‐sectional SEM images of nanowire in PAM. h) Representative high‐resolution transmission electron microscope (TEM) image of nanowire. i) Photo of polydimethylsiloxane socket assisting the alignment of liquid metal wires. Reproduced with permission.^{[ 120a ]} Copyright 2020, Nature Publishing Group.

Figure 17

Noninvasive delivery of nucleic acids (NAs) upon octopus‐like flexible vector for retinoblastoma treatment. a) Construction of polyplexes by a simple mixing of multivalent penetratin (MVP) and NAs, for example, siRNA or antisense oligonucleotides (ASO). b) Several cationic penetratin tentacles in the polyplexes can freely bind with anionic NAs, whereas others regulated the noninvasive intraocular delivery, similar to an octopus carrying NAs and moving forward. c) TEM images showed the morphology of polyplexes. Scale bar, 200 nm. d) Intraocular distribution of ASO delivered by 8‐valent penetratin (8VP) polyplexes in the whole mice eyes including retinas and corneas. e) Establishment and therapy of retinoblastoma‐bearing mice model. f) Semiquantitative inhibition effects of different polyplexes on bioluminescence expression of the tumor. Reproduced with permission.^{[ 123 ]} Copyright 2019, American Chemical Society.

Figure 18

Noninvasive permanent refractive error correction by femtosecond laser‐triggered reactive oxygen species (ROS) generation. a) Schematic illustration of laser‐assisted therapeutic process, which is associated with the low‐density plasma production, ROS, and cross‐link formation. b,c) Differences in structure between control and laser‐treated pig eyes. Two‐photon fluorescence (TPF) images of the cross‐sections of control (b) and laser‐treated (c) pig eyes. There are three zones imaged in the laser‐treated eye: an untreated zone (left), a transitional zone (middle), and the central zone (right). Crosslink density in control eyes is similar to that in untreated zone of the laser‐irradiated specimen. Scale bars, 60 µm. Reproduced with permission.^{[ 129 ]} Copyright 2018, Nature Publishing Group.

Figure 19

Chain‐like gold nanoparticle (CGNP) clusters for multimodal photoacoustic microscopy (PAM) and OCT enhanced molecular imaging. Experimental setup of PAM and OCT equipment. a) Schematic illustration of the imaging system. b) Physical setup. In PAM mode, nanosecond excitation laser (450–710 nm) delivered and focused onto the retina. To enable multimodal imaging, the excitation laser beam utilized to induce photoacoustic signal was coaxially aligned with OCT multispectral luminescence with a center wavelength at 805 and 905 nm. The generated acoustic signal was detected by a needle‐shaped hydrophone ultrasonic transducer, and the recorded data was used to reconstruct PAM images. A spectrometer was used to detect the reflected OCT light interfered with the reference light and the interference intensity spectra. Retina was scanned by a galvanometer. c) Illustration of in vivo multimodal imaging after intravenous injection of CGNP clusters‐RGD into the rabbit model. Photoacoustic signals from rabbit retina was produced using nanosecond pulsed laser illumination at 578 or 650 nm. Reproduced under the terms of the CC‐BY 4.0 license.^{[ 132 ]} Copyright 2020, The Authors. Published by Nature Publishing Group.

Figure 20

Nanomaterial exposure induced typical eye‐related disorders. Once ocular tissues contact with nanomaterials, potential toxic effects caused by nanomaterials could occur on ocular surface (e.g., cornea), within the eye (e.g., lens and iris) or inner surface of retina, macula optic, and nerve. Reproduced under the terms of the Creative Commons CC‐BY license.^{[ 56 ]} Copyright 2019, The Authors. Published by Wiley‐VCH.

Figure 21

Summary of ocular nanomedicine. The underlying principles of ocular nanomedicine biochemistry play an essential role in determining their subsequent ophthalmologic applications. However, to fulfill specific theranostic goals, some critical challenges remain to be addressed, and corresponding future directions on the developments of ocular nanomedicine need to be clarified.