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》

Dual-Atom Nanozyme Eye Drops Attenuate Inflammation and Break the Vicious Cycle in Dry Eye Disease.

Dry eye disease (DED) is a major ocular pathology worldwide, causing serious ocular discomfort and even visual impairment. The incidence of DED is gradually increasing with the high-frequency use of electronic products. Although inflammation is core cause of the DED vicious cycle, reactive oxygen species (ROS) play a pivotal role in the vicious cycle by regulating inflammation from upstream. Therefore, current therapies merely targeting inflammation show the failure of DED treatment. Here, a novel dual-atom nanozymes (DAN)-based eye drops are developed. The antioxidative DAN is successfully prepared by embedding Fe and Mn bimetallic single-atoms in N-doped carbon material and modifying it with a hydrophilic polymer. The in vitro and in vivo results demonstrate the DAN is endowed with superior biological activity in scavenging excessive ROS, inhibiting NLRP3 inflammasome activation, decreasing proinflammatory cytokines expression, and suppressing cell apoptosis. Consequently, the DAN effectively alleviate ocular inflammation, promote corneal epithelial repair, recover goblet cell density and tear secretion, thus breaking the DED vicious cycle. Our findings open an avenue to make the DAN as an intervention form to DED and ROS-mediated inflammatory diseases.

Chu D ，Zhao M ，Rong S ，Jhe W ，Cai X ，Xiao Y ，Zhang W ，Geng X ，Li Z ，Zhang X ，Li J ... -  《-》

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 ... -  《-》

ROS-responsive celastrol-nanomedicine alleviates inflammation for dry eye disease.

Dry eye disease (DED) is a major global eye disease leading to severe eye discomfort and even vision impairment. The incidence of DED has been gradually increasing with the high frequency of use of electronic devices. It has been demonstrated that celastrol (Cel) has excellent therapeutic efficacy in ocular disorders. However, the poor water solubility and short half-life of Cel limit its further therapeutic applications. In this work, a reactive oxygen species (ROS) sensitive polymeric micelle was fabricated for Cel delivery. The micelles improve the solubility of Cel, and the resulting Cel loaded micelles exhibit an enhanced intervention effect for DED. Thein vitroresults demonstrated that Cel-nanomedicine had a marked ROS responsive release behavior. The results ofin vitroandin vivoexperiments demonstrated that Cel has excellent biological activities to alleviate inflammation in DED by inhibiting TLR4 signaling activation and reducing pro-inflammatory cytokine expression. Therefore, the Cel nanomedicine can effectively eliminate ocular inflammation, promote corneal epithelial repair, and restore the number of goblet cells and tear secretion, providing a new option for the treatment of DED.

Cui B ，Zhang N ，Zhang W ，Ning Q ，Wang X ，Feng H ，Liu R ，Li Z ，Li J ... -  《-》