Cannabis sativa has served a dual role in history: as medicine and as a psychoactive agent, which established it as one of the most globally utilized drugs [11], [49]. Growing evidence suggests that cannabinoids hold promise for alleviating chronic pain, spasticity, weight loss, nausea, and vomiting [11], [53]. Since the 1970 s, research has explored their potential in lowering intraocular pressure and for their anti-inflammatory and neuroprotective effects [18], [26].

Retinal ischemia is characterized by a reduction in blood flow to the retinal tissues, leading to insufficient oxygen and nutrient transportation. This condition makes the retina particularly vulnerable to damage due to its high metabolic demand [25], [45]. The decreased blood supply often results from the occlusion or narrowing of retinal arteries, veins, or capillaries, which can be caused by factors such as emboli, thrombosis, vasospasms, or systemic conditions like hypertension and diabetes mellitus. The resulting lack of blood flow triggers a cascade of biochemical events, including oxidative stress, inflammation, and neuronal apoptosis, ultimately leading to cellular damage and significantly contributing to various ocular pathologies that cause vision loss and blindness [45]. Agents capable of counteracting oxidative stress serve as neuroprotectants [45].

Cannabidiol (CBD), a non-psychoactive compound derived from Cannabis sativa, shows promise in treating retinal ischemia due to its previously described combined anti-inflammatory and neuroprotective effects [6], [42]. However, despite its therapeutic potential, there are few CBD-approved medications on the market, likely due to challenges such as low bioavailability, susceptibility to light degradation, and poor water solubility [46]. The majority of safety and efficacy data related to CBD pertains to its oral administration [58]. As interest in utilizing CBD for treating ocular pathologies grows, there is a pressing need to explore alternative routes of administration that have received limited attention thus far.

Most neuroprotective drugs for optic neuropathies are administered as eye drops, but less than 5 % of the drug penetrates the cornea, necessitating high doses and repeated administration leading to increasing costs [13], [35]. Once the drug passes through the cornea and lens, it must diffuse through the aqueous and vitreous humor to reach retinal ganglion cell receptors, reducing efficacy. There is a need for improved ocular drug delivery systems, especially for neuroprotective therapies. While cannabinoids have suggested neuroprotective effects, challenges in delivering them to the retina and their low bioavailability have hindered progress. Previous topical formulations, such as mineral oil, hydrogel or cyclodextrins, have been cytotoxic or irritating [27], [28], [33], [34], [37]and are mainly applied for diseases affecting the ocular surface and anterior segment of the eye. Intravitreal administration has gained acceptance because it can deliver therapeutic drugs directly into the vitreous [12]. Considering that there may be a need for repeated injections, niosomes could be an alternative to maintain the therapeutic level of the substance for some period.

Niosomes are vesicular systems formed by amphiphilic non-ionic surfactants and cholesterol in an aqueous medium that have the unique ability to encapsulate both hydrophilic and hydrophobic compounds [3], [16]. This capability enhances the bioavailability of hydrophobic substances while protecting them from rapid degradation [50], [60].

Building on the limitations of existing ocular drug delivery methods and the challenges associated with CBD administration, this study explores the use of niosomes loaded with CBD as an innovative and promising formulation. By leveraging the unique encapsulation properties of niosomes and the therapeutic potential of CBD, this approach aims to overcome key barriers such as low bioavailability, reduced stability, and limited targeted delivery to the retina. Thus, this study aimed to assess whether CBD-loaded niosomes could be an effective formulation for neuroprotection of the retina in an animal model of ischemic injury induced by a sudden increase in intraocular pressure (IOP).