Advances in development of exosomes for ophthalmic therapeutics (2023)


Nowadays, the lives of more than 2.2 billion people in the world are seriously affected by visual disorders and diseases, and vision disorders rank as the third disease affecting people's quality of life after tumors and cardiovascular disease, on the basis of the world health organization (WHO) [1]. Management of ocular diseases mainly include surgery and pharmacotherapy. Nowadays, surgical techniques, including vitrectomy, corneal transplantation, cataract removal, and implant of artificial lens, are usually performed in the late stage of diseases with severe fibrosis, hemorrhage, uncontrolled high intraocular pressure, or irreversible degeneration [2], [3], [4]. Due to the traumatic nature of surgery, vision prognosis and postoperative recovery are unsatisfactory in a large number of patients. For example, despite advancements in vitrectomy, visual outcomes kept unchanged or declined in as high as 43.7% of eyes with advanced proliferative diabetic retinopathy (DR), and 12.4% of eyes experienced anatomic failure [5]. Therefore, pharmacotherapy is more essential than ever, even in the fields where surgery was considered the only means, such as retinal detachment [6].

Current opinions of ophthalmology emphasize early intervention instead of management of complications at later stages, either for ocular surface diseases, or vitreoretinal diseases, to maintain visual functions and ocular comfort levels [7], [8]. However, traditional ocular drug delivery methods including topical eye drops/ointments or local injection, and oral or intravenous administration, needed to be improved. Firstly, it has a low efficiency and poor targeting rate. For example, eye drops/ointments are rapidly drained from the ocular cavity due to tear flow and lachrymal nasal drainage. Only a tiny amount is available and frequent dosing is demanded. Besides, drug distribution into the retina is later constrained by the retinal pigment epithelium (RPE) and retinal endothelia, despite the fact that medicines can easily enter the choroidal extravascular space via intravenous or oral routes. As a result, without precise targeting technologies, only a very small portion of the therapeutic dose can reach the retina [9]. Secondly, traditional ocular drug types, including chemical drugs and biological agents, are faced with a short half-life and side effects. In general, biological drugs have a longer half-life than chemicals in the vitreous cavity. Even so, biological agents are still insufficient for the whole duration of disease treatment. For example, as a biological agent, ranibizumab against vascular endothelial growth factor (VEGF) to treat age-related macular degeneration (AMD) by monthly intravitreal injection has a half-life of 2.5 to 3 days [10]. Moreover, the treatment of autoimmune uveitis commonly includes systemic or locally administered corticosteroids, with their long-term use limited by significant side effects. Therefore, efforts have been put in to improve the management effect of ophthalmic diseases.

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In the past decade, numerous breakthroughs have been made in the discovery of novel therapies. Among them, cell-based therapeutics are rapidly advancing. Compared with traditional drug therapy, long-term efficacy and excellent biocompatibility are two significant advantages of cell therapy. They can alter the microenvironment through paracrine actions to cause indirect effects in addition to direct effects [11]. Achievements have been made in the application of ophthalmic therapeutics. For example, intravitreal injection of mesenchymal stromal cells (MSCs) during pars plana vitrectomy (PPV) has been used to treat large macular holes (MHs) in clinical patients. It has achieved ideal results of ∼80% holes-closed rate, while up to 44% of large MHs remained open after regular PPV [12]. Nonetheless, applying cell-based therapeutics in ophthalmology encountered a series of problems. From a medical perspective, low oxygen tension, nutrient deprivation, and inflammation lead to low survival rates of therapeutic cells after intravitreal injection and thereby result in limited therapeutic effects [13]. Additionally, there is a possibility that stem cells will differentiate into unwanted cells like myofibroblasts, which could have negative treatment outcomes and adverse effects [14]. This limits the clinical feasibility of these cell-based technologies, so scientists wonder whether cell-derived products may be sufficient for ophthalmic therapeutics. Among products released by cells, exosomes have caught the scientific community’s attention.

In view of good biocompatibility, low cytotoxicity, immunological inertness, specific targeting capability, and the capability of crossing biological barriers, exosomes are potential therapeutics for diseases. Exosome therapy has appeared in treating a wide range of diseases, including cancer, heart disease, nervous system disease, arthritis, and kidney disease. For example, the cardiovascular efficacy of exosomes from various cellular sources, such as MSCs [15], inert fibroblast [16], cardiac progenitor cells [17], [18], and cardiomyocytes [19], have been evaluated in mice, rats, and pigs through intravenous or intramyocardial administration. Moreover, the results showed that the beneficial effect of heart failure treatment was ultimately achieved by improving cardiac regeneration, promoting angiogenesis, inhibiting inflammation, and so forth. In addition to native exosome therapeutics, technologies have been developed to modulate exosomes and improve their bioactivity, stability, targeting, and presentation to augment the therapeutic efficacy, such as cancer therapy [20], [21]. Furthermore, due to the feature that exosomes are natural carriers for cell–cell communication, researchers are allured to develop exosome-based drug delivery systems [22], [23]. Similar to the fields mentioned above, exosomes, either as a therapeutic agent or as a drug delivery system, have been widely explored for ophthalmic therapeutics during the past decade.

As a drug delivery system, exosomes outperform other delivery platforms such as lipid nanoparticles, liposomes, and polymeric nanomicelles when it comes to disease-related applications[24]. The major advantages are as follows: (1) high targeting capacity increases drug use efficiency and decreases drug use frequency through passive and active targeting methods [25]; (2) low immunogenicity is promoted by autogenous exosomes, which decreases body clearance [26]; (3) high drug loading capacity, as well as loading efficiency including a variety of loading cargoes like nucleic acids, proteins and small molecules [27]; (4) therapeutic potential to produce joint, synergistic therapeutic outcome [28]; and (5) sustaining high stability over time, multiple drug release and effective drug solubility enhancement [24]. All these benefits have increased their use in biomedical fields.

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This review presents the biophysical properties, origin, membrane composition, cargos of exosomes, and various techniques used for the isolation, characterization, and bioengineering of exosomes (Figure 1). Focusing on the utilization of exosomes as delivery vectors for treatment, we review the recent advances of exosomes applied in the ophthalmic therapeutics field. Finally, we offer perspectives on current limitations, challenges, and opportunities and discuss potential directions toward future research and clinical translation of exosomes.

Section snippets

Overview of exosomes

Exosomes, membrane-bound vesicles of 30–150 nm in diameter, have been found to play a significant role in the physiology and pathology of many organs, including the eye. In 1983, Harding and Johnstone contributed to the discovery that transferrin receptors, associated with small vesicles, were released from sheep maturing blood reticulocytes to the outside of the cell by process of receptor-mediated endocytosis and recycling [29]. Afterward, in 1987, Johnstone named it “exosomes” for the first

Corneal damage

The corneal opacity ranks fourth among the global population with moderate or severe vision impairment nowadays [63]. Healing corneal defects is a complex process involving cell death, migration, proliferation, differentiation, and extracellular matrix remodeling [64]. In the clinic, despite the frequent use of artificial tears, artificial tear ointment, or even autologous serum eyedrops, etc., corneal epithelium defects secondary to the neurotrophic keratopathy or the ocular graft-versus-host

Exosomes as delivery vectors

The drug delivery system has become a research hotspot in the field of biomedicine. Scientists keep optimizing drug delivery systems since the 1970s. Delivery platforms, such as lipid nanoparticles (LNPs), liposomes, polymeric nanoparticles and inorganic nanoparticles — collectively known as nanomedicines — deliver drugs to specific cells or organs [200]. More than 20 nanomedicines are now FDA- approved for myriad diseases including cancer, hepatitis C and haemophilia. Although they have a

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Interfering of neural communication

Although exosomes have multiple therapeutic applications in ophthalmology diseases, potential risks associated with their ocular use should not be overlooked. Specifically, internal communication between neurons is worthy of attention because the optic nerve plays a key role in visual imaging and cannot be regenerated once injured. Even though exosome-related optic nerve injury is barely reported, neural injury still exists in the central never system. For instance, neural communication can be

Conclusion and future perspective

In general, exosomes are a promising, cell-free, robust and customizable translational approach to improve the outcomes of patients with ophthalmic diseases. Over the past decade, understanding the biology of exosomes and their application in the field of ophthalmic therapeutics has made significant strides. We now have a greater comprehension of the biophysical properties, origin, composition, isolation and characterization of exosomes. Regarding the application of exosomes, significant

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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This work was supported by the National Natural Science Foundation of China [82070948,82101138], the Capital Health Research and Development of Special [SF2022-2-2035], and Beijing Hospitals Authority's Ascent Plan [DFL20220301].

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