Diabetic retinopathy (DR) is a predominant etiology of vision loss across the globe, characterized mainly by oxidative stress and vascular damage [1], that triggers inflammation, excitotoxicity, and also reduces neurotrophins, leading to immense neurodegeneration [2]. According to the National Diabetes and Diabetic Retinopathy Survey (NDDRS) 2024, India currently has over 145 million people with diabetes, and this statistic is anticipated to reach till 350 million by 2040. Approximately 18 % of these individuals are affected by DR [3,4]. DR arises majorly from ocular neovascularization, which originates from the venous side of the retinal circulation and may extend through the inner limiting membrane into the vitreous [5]. These newly formed blood vessels are fragile, prone to leakage, and eventually become surrounded by fibrous connective tissues, that have the possibility to adhere to the surrounding collagenous structures, leading to vitreous haemorrhage and/or retinal detachment [6,7]. However, the major underlying mechanism behind DR is complicated and still not completely understood. Moreover, the current therapy majorly encompasses continuous intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents like aflibercept, bevacizumab, and ranibizumab that possess a short t½ of approximately 5–7 days [8]. As a consequence, repeated invasive intravitreal injections are needed in order to maintain the desired drug concentration in the vitreous humor, which is further associated with various ocular complications like endophthalmitis [9], retinal detachment [10], vitreous haemorrhage [11], macular edema [12] or neovascular glaucoma [13]. These complications necessitate the urgent need to understand the current advancements in novel therapeutics and in targeting novel anti-angiogenic agent to the retina, which could offer greater efficacy and also is convenient for patients from economic perspective.

Calcium dobesilate (CD) (calcium 2, 5-dihydroxybenzenesulfonate) is one such angio-protective agent that has efficiently demonstrated slowing down the progression of DR in several randomized clinical trials [14]. When administered systemically, it ameliorated the endothelial activity by significantly reducing the serum levels of endothelin-1 thus proving to possess efficient anti-angiogenic activity against neurodegeneration [15]. CD has been shown to inhibit the diabetes-induced increase in retinal NF-кB, ILs, TNF-α, and also oxidative stress in experimental animal models [16]. Moreover, the retinal downregulation of PKC-delta-P38 MAPK and VEGF are key mechanisms by which CD inhibits the disruption of the blood-retinal barrier [17]. Also, it has the potential to decrease blood hyper-viscosity, inhibit the synthesis and release of platelet aggregators, improve retinal microangiopathy and haemorrhage, and subsequently enhance microcirculatory disturbances [18]. However, very limited research is done to explore the therapeutic activity of CD post topical application using nanotechnology in DR. Emerging breakthroughs in nanotechnology holds immense potential for the development of advanced therapy options for retinal vascular diseases with enhanced bioavailability and improved targeted therapy.

Liquid crystals (LCs) are one such highly adaptable and effective bicontinuous lipid-based nano-structured systems that are colloidally dispersed in aqueous media in the presence of appropriate surfactants and stabilizers [19]. They possess higher structural similarity to that of the bio-membranes, that facilitate its fusion with the lipid bilayers of the corneal epithelia thereby increasing corneal residence time, thus making it an ideal candidate for ocular drug delivery [20]. Studies by Wu et al. demonstrated that corneal permeation of dexamethasone using in-situ LC gel showed a significant enhancement in Papp value by 5.45 times when compared with dexamethasone sodium phosphate eye drops, with longer ocular retention time. The study also demonstrated better biocompatibility of LCs with longer corneal retention time than aqueous solution of dexamethasone [21]. Also, studies conducted by Sharadha et al. demonstrated higher concentration of Triamcinolone acetonide in LCs in the retina post subconjunctival therapy in rats, confirmed by approximately 100.85 % of Triamcinolone acetonide recovery from the retina confirming enhanced permeation. Thereby, LCs were recognized as effective and potential nanocarriers with the potential for targeted retinal delivery [22]. Moreover, the selection of MO (monoolein), P407 (poloxamer 407), and PEG400 as key formulation parameters is rooted in their critical roles in liquid crystalline g phase behaviour and stability. Moreover, the development of LCs using MO has currently emerged as one of the most extensively researched amphiphilic molecules targeting the posterior segment of the eye due to its non-toxicity, excellent mucosal adhesion, and strong biocompatibility [23]. It helps in forming the core cubic phase structure, which is essential for drug entrapment and controlled release, while P407 stabilizes the LC nanoparticles by integrating into the bilayer or adsorbing to the surface, preventing aggregation and ensuring uniform particle size. It also enables the lipids to self-assemble and organize into micelle-like structure and crystal nucleation growth offering enhanced solubility of any kind of drug and thereby enabling controlled drug release, demonstrated by Zhang et al. [24]. Additionally, Kadhum et al. demonstrated the excellent use of PEG 400 as chemical permeation enhancer to dramatically enhance the drug permeation rates by 8- fold from hexosome with the incorporation of PEG 400 along with glyceryl monooleate [25]. Therefore, by incorporating components like monoolein, P407 and PEG 400 to develop LCs could efficiently surpass other lipid and polymeric-based nanoparticles owing to their significantly higher surface area, sustained drug release matrix, lesser ocular irritation, ability to self-assemble, thermal stability, enhanced drug permeation rates and outstanding encapsulation efficiency. PEG400 acts as a solubilizer and solvent, enhancing drug loading and modulating the internal crystalline phase by influencing the hydration and molecular arrangement of MO. These parameters collectively govern the LC's nanostructure, stability, and drug release profile: MO concentration dictates the cubic phase integrity, P407 optimizes particle size and prevents phase separation, and PEG400 balances solubility and phase transitions (e.g., lamellar to cubic). Their interplay ensures reproducible and biocompatible LC formulations suitable for pharmaceutical applications.

The major goal of this research is to examine and investigate the neuroprotective potential of CD-LCs in treating DR that has not been researched before. Also, no studies have been done for examining the activity of CD locally in the retinal cells. Moreover, this study is designed to study the topical delivery of CD-LCs which is expected to enhance the corneal residence time thereby increasing transcorneal permeability, targeting the retina, thereby, leading to the successful designing of a promising non-invasive drug delivery system. However, based on the current knowledge and information available to us, such formulation has not yet been designed to treat or manage DR, thereby, this study could offer valuable perspectives for applications in clinical settings.