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

作者全名：Xia, Yuanyou; Zhang, Yu; Du, Yangrui; Wang, Zhigang; Cheng, Long; Du, Zhiyu

作者地址：[Xia, Yuanyou; Zhang, Yu; Du, Yangrui; Du, Zhiyu] Chongqing Med Univ, Dept Ophthalmol, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Xia, Yuanyou; Wang, Zhigang; Cheng, Long] Chongqing Med Univ, Chongqing Key Lab Ultrasound Mol Imaging, Affiliated Hosp 2, Chongqing 400010, Peoples R China; [Xia, Yuanyou] Chongqing Med Univ, State Key Lab Ultrasound Med & Engn, Chongqing 400010, Peoples R China

通信作者：Du, ZY (通讯作者)，Chongqing Med Univ, Dept Ophthalmol, Affiliated Hosp 2, Chongqing 400010, Peoples R China.

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001217429500003

JCR分区：Q1

影响因子：10.6

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Ocular adhesive; Anti-inflammation; Anti-oxidation; Mitochondrial metabolites; Dry eye

摘要：Background 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.Results 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-1 beta, IL-6, and TNF-alpha). 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.Conclusion 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.

基金机构：Program for Leading Talents of Medical Innovation in Chongqing municipality [CQYC20200303112]

基金资助正文：This work was financially supported by the grant from the Program for Leading Talents of Medical Innovation in Chongqing municipality (No. CQYC20200303112).