Abstract：
Dry eye disease (DED) is a prevalent ocular disorder characterized by unstable tear film condition with loss of aqueous or mucin, excessive oxidative stress, and inflammation, leading to discomfort and potential damage to the ocular surface. Current DED therapies have shown restricted therapeutic effects such as frequent dosing and temporary relief with potential unwanted side effects, urgently necessitating the development of innovative efficient therapeutic approaches. Herein, we developed rosmarinic acid (RosA) conjugated gelatin nanogels loading diquafosol sodium (DQS), DRGNG, for simultaneous ROS-scavenging and mucin-secreting DED treatment. Mechanically, DRGNG suppressed the ROS production, reduced inflammatory factors, and prompted mucin secretion in vitro and in vivo. The whole transcriptome RNA sequencing in vitro further provided a detailed analysis of the upregulation of anti-oxidant, anti-inflammatory, and mucin-promotion pathways. Therapeutically, both in evaporative DED and aqueous deficient DED models, the dual-functional DRGNG could prolong the retention time at the ocular surface, efficiently suppress the oxidative stress response, reverse ocular surface morphology, and recover tear film homeostasis, thus alleviating the DED when the dosage is halved compared to the commercial Diquas®. Our findings contribute to developing innovative therapies for DED and offer insights into the broader applications of nanogels in ocular drug delivery and oxidative stress-related conditions.
摘要：
干眼症（DED）是一种常见的眼部疾病，其特征是泪膜不稳定，水性或粘蛋白丢失，过度的氧化应激，和炎症，导致眼表不适和潜在损害。目前的DED疗法已显示出有限的治疗效果，例如频繁给药和暂时缓解，并具有潜在的不良副作用。迫切需要开发创新有效的治疗方法。在这里，我们开发了装载diquafosol钠（DQS）的迷迭香酸（RosA）共轭明胶纳米凝胶，DRGNG,用于同时清除ROS和分泌粘蛋白的DED治疗。机械上,DRGNG抑制了ROS的产生，减少炎症因子，并促进粘蛋白在体外和体内的分泌。体外全转录组RNA测序进一步提供了对抗氧化剂上调的详细分析,抗炎,和粘蛋白促进途径。治疗学上,在蒸发DED和水缺乏DED模型中，双功能DRGNG可以延长在眼表的保留时间，有效抑制氧化应激反应，逆眼表形态学，恢复泪膜稳态，因此，与市售Diquas®相比，当剂量减半时，DED减轻。我们的发现有助于开发DED的创新疗法，并为纳米凝胶在眼部药物递送和氧化应激相关疾病中的更广泛应用提供了见解。
