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.

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.

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.