Comprehensive dry eye therapy: overcoming ocular surface barrier and combating inflammation, oxidation, and mitochondrial damage.

Dry Eye Disease (DED) is a prevalent multifactorial ocular disease characterized by a vicious cycle of inflammation, oxidative stress, and mitochondrial dysfunction on the ocular surface, all of which lead to DED deterioration and impair the patients' quality of life and social functioning. Currently, anti-inflammatory drugs have shown promising efficacy in treating DED; however, such drugs are associated with side effects. The bioavailability of ocular drugs is less than 5% owing to factors such as rapid tear turnover and the presence of the corneal barrier. This calls for investigations to overcome these challenges associated with ocular drug administration. A novel hierarchical action liposome nanosystem (PHP-DPS@INS) was developed in this study. In terms of delivery, PHP-DPS@INS nanoparticles (NPs) overcame the ocular surface transport barrier by adopting the strategy of "ocular surface electrostatic adhesion-lysosomal site-directed escape". In terms of therapy, PHP-DPS@INS achieved mitochondrial targeting and antioxidant effects through SS-31 peptide, and exerted an anti-inflammatory effect by loading insulin to reduce mitochondrial inflammatory metabolites. Ultimately, the synergistic action of "anti-inflammation-antioxidation-mitochondrial function restoration" breaks the vicious cycle associated with DED. The PHP-DPS@INS demonstrated remarkable cellular uptake, lysosomal escape, and mitochondrial targeting in vitro. Targeted metabolomics analysis revealed that PHP-DPS@INS effectively normalized the elevated level of mitochondrial proinflammatory metabolite fumarate in an in vitro hypertonic model of DED, thereby reducing the levels of key inflammatory factors (IL-1β, IL-6, and TNF-α). Additionally, PHP-DPS@INS strongly inhibited reactive oxygen species (ROS) production and facilitated mitochondrial structural repair. In vivo, the PHP-DPS@INS treatment significantly enhanced the adhesion duration and corneal permeability of the ocular surface in DED mice, thereby improving insulin bioavailability. It also restored tear secretion, suppressed ocular surface damage, and reduced inflammation in DED mice. Moreover, it demonstrated favorable safety profiles both in vitro and in vivo. In summary, this study successfully developed a comprehensive DED management nanosystem that overcame the ocular surface transmission barrier and disrupted the vicious cycle that lead to dry eye pathogenesis. Additionally, it pioneered the regulation of mitochondrial metabolites as an anti-inflammatory treatment for ocular conditions, presenting a safe, efficient, and innovative therapeutic strategy for DED and other inflammatory diseases.

Xia Y ，Zhang Y ，Du Y ，Wang Z ，Cheng L ，Du Z ... -  《JOURNAL OF NANOBIOTECHNOLOGY》

Biochanin A: Disrupting the inflammatory vicious cycle for dry eye disease.

Dry eye disease (DED) is a complex disorder driven by several factors like reduced tear production, increased evaporation, or poor tear quality. Oxidative stress plays a key role by exacerbating the inflammatory cycle. Previous studies explored antioxidants for DED treatment due to the link between oxidative damage and inflammation. Biochanin A (BCA) is a bioisoflavone from red clover with potent anti-inflammatory effects. This study investigated BCA's therapeutic potential for DED. Human corneal epithelial cells were cultured under hyperosmotic conditions to mimic DED. BCA treatment increased cell viability and decreased apoptosis and inflammatory cytokine expression. A DED mouse model was developed using female C57BL/6 mice in a controlled low-humidity environment combined with scopolamine injections. Mice received eye drops containing phosphate-buffered saline, low-dose BCA, or high-dose BCA. The effectiveness was evaluated by measuring tear volume, fluorescein staining, eye-closing ratio, corneal sensitivity and PAS staining. The levels of inflammatory components in corneas and conjunctiva were measured to assess DED severity. Maturation of antigen-presenting cells in cervical lymph nodes was analyzed by flow cytometry. BCA eye drops effectively reduced inflammation associated with DED in mice. BCA also decreased oxidative stress levels by reducing reactive oxygen species and enhancing the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2). These findings demonstrate that BCA ameliorates oxidative stress and ocular surface inflammation, indicating potential as a DED treatment by relieving oxidative damage and mitigating inflammation.

Chen T ，Zhou N ，Liang Q ，Li Q ，Li B ，Chu Y ，Zhang D ，Chen Z ，Tsao JR ，Feng X ，Hu K ... -  《-》

A tissue-adhesive F127 hydrogel delivers antioxidative copper-selenide nanoparticles for the treatment of dry eye disease.

Ou L ，Wu Z ，Hu X ，Huang J ，Yi Z ，Gong Z ，Li H ，Peng K ，Shu C ，Koole LH ... -  《-》

Capsanthin from Capsicum annum fruits exerts anti-glaucoma, antioxidant, anti-inflammatory activity, and corneal pro-inflammatory cytokine gene expression in a benzalkonium chloride-induced rat dry eye model.

Dry eye disease (DED) is a complex ocular surface inflammatory disease. Its occurrence varies widely over the world, ranging from 5% to 34%. The use of preservatives, specifically benzalkonium chloride, in the ocular drops worsens the DED conditions. Furthermore, the Covid-19 pandemic increased screen time and the use of face masks and shields. As a result, the number of people suffering from dry eye disease (DED) has increased significantly in recent years. The main objective of our study is to find a solution to manage the dry eye disease (DED) preferably from natural source without any adverse events. In this study, the beneficial effects of capsanthin from Capsicum annum (CCA) were evaluated on benzalkonium chloride (BAC)-induced dry eye disease (DED) in Albino Wistar rats. Oral supplementation of CCA resulted in a statistically significant decrease in intraocular pressure (IOP) (p < .0001), increase in tear break-up time (TBUT) (p < .01), decline in Schirmer test results (p < .01), and decrease in corneal surface inflammation (p < .01). Capsanthin ameliorated in reducing oxidative stress by increasing serum antioxidant levels such as glutathione peroxidase (GPX), nitric oxide (NO), and lactoferrin (LTF) and inhibiting matrix metalloproteinases 2 and 9 (MMP2 and MMP9) (p < .0001). Capsanthin treatment significantly inhibited the expression of inflammatory cytokines, tumor necrosis factor-alpha (TNF-α), interleukins (IL-2, IL-4, IL-6), and pro-inflammatory mediator, matrix metalloproteinase-9 (MMP9). Furthermore, the lacrimal gland expressed vascular cell adhesion molecule (VCAM-1), and prostaglandin-endoperoxide synthase 2 (PTGS2) was suppressed by CCA treatment. PRACTICAL APPLICATIONS: Benzalkonium chloride (BAC), a preservative widely used in the topical ocular drug delivery system (ODDS), causes undesirable effects such as dry eye disease as well as ameliorating intraocular pressure leading to optical nerve damage and irreversible vision loss. Capsanthin from Capsicum annum (CCA) can be used to treat symptoms related to dry eye disease such as inflammation, eye irritation, visual disturbance, ocular discomfort with potential damage to the ocular surface. The CCA may be beneficial in the treatment of glaucoma, an elevated intraocular pressure. Capsanthin from C. annum can be useful in managing DED by increasing tear break-up time (TBUT), declining in Schirmer test results and decreasing in corneal surface inflammation.

Shanmugham V ，Subban R 《-》

Anti-Oxidative and Anti-Inflammatory Micelles: Break the Dry Eye Vicious Cycle.

Dry eye disease (DED) impacts ≈30% of the world's population and causes serious ocular discomfort and even visual impairment. Inflammation is one core cause of the DED vicious cycle, a multifactorial deterioration in DED process. However, there are also reactive oxygen species (ROS) regulating inflammation and other points in the cycle from the upstream, leading to treatment failure of current therapies merely targeting inflammation. Accordingly, the authors develop micelle-based eye drops (more specifically p38 mitogen-activated protein kinases (MAPK) inhibitor Losmapimod (Los)-loaded and ROS scavenger Tempo (Tem)-conjugated cationic polypeptide micelles, designated as MTem/Los) for safe and efficient DED management. Cationic MTem/Los improve ocular retention of conjugated water-soluble Tem and loaded water-insoluble Los via electrostatic interaction with negatively charged mucin on the cornea, enabling an increase in therapeutic efficiency and a decrease in dosing frequency. Mechanistically, MTem/Los effectively decrease ROS over-production, reduce the expression of proinflammatory cytokines and chemokines, restrain macrophage proinflammatory phenotypic transformation, and inhibit cell apoptosis. Therapeutically, the dual-functional MTem/Los suppress the inflammatory response, reverse corneal epithelial defect, save goblet cell dysfunction, and recover tear secretion, thus breaking the vicious cycle and alleviating the DED. Moreover, MTem/Los exhibit excellent biocompatibility and tolerability for potential application as a simple and rapid treatment of oxidative stress- and inflammation-induced disorders, including DED.

Li S ，Lu Z ，Huang Y ，Wang Y ，Jin Q ，Shentu X ，Ye J ，Ji J ，Yao K ，Han H ... -  《Advanced Science》