Retinal cell-targeted liposomal ginsenoside Rg3 attenuates retinal ischemia-reperfusion injury via alleviating oxidative stress and promoting microglia/macrophage M2 polarization

• Published in: Free radical biology & medicine 2023-09, Vol.206, p.162-179
• Main Authors: Huang, Yanmei, Lu, Jing, Zhao, Laien, Fu, Xiaoxuan, Peng, Shengjun, Zhang, Wen, Wang, Rong, Yuan, Wenze, Luo, Rongrui, Wang, Xiaojie, Li, Zelin, Zhang, Zhuhong
• Format: Article
• Language: English
• Subjects: Anti-inflammatory therapy; Ginsenoside Rg3; M1/M2 re-polarization; Oxidative stress; RIR injury
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2023.06.024

Retinal ischemia-reperfusion (RIR) injury remains a major challenge that is detrimental to retinal cell survival in a variety of ocular diseases. However, current clinical treatments focus on a single pathological mechanism, making them unable to provide comprehensive retinal protection. A variety of natural products including ginsenoside Rg3 (Rg3) exhibit potent antioxidant and anti-inflammatory activities. Unfortunately, the hydrophobicity of Rg3 and the presence of various intraocular barriers limit its effective application in clinical settings. Hyaluronic acid (HA)- specifically binds to cell surface receptors, CD44, which is widely expressed in retinal pigment epithelial cells and M1-type macrophage. Here, we developed HA-decorated liposomes loaded with Rg3, termed Rg3@HA-Lips, to protect against retinal damage caused by RIR injury. Treatment with Rg3@HA-Lips significantly inhibited the oxidative stress induced by RIR injury. In addition, Rg3@HA-Lips promoted the transition of M1-type macrophage to the M2 type, ultimately reversing the pro-inflammatory microenvironment. The mechanism of Rg3@HA-Lips was further investigated and found that they can regulateSIRT/FOXO3a, NF-κB and STAT3 signaling pathways. Together with as well demonstrated good safety profiles, this CD44-targeted platform loaded with a natural product alleviates RIR injury by modulating the retinal microenvironment and present a potential clinical treatment strategy. [Display omitted] •We prepared CD44-targeted ginsenoside Rg3-loaded liposomes.•Rg3@HA-Lips inhibited oxidative stress and inflammation in RIR injury in vitro and in vivo.•Rg3@HA-Lips promoted the transition of microglia/macrophage phenotype from M1 to M2.•Rg3@HA-Lip activated SIRT1/FOXO3a signaling pathway and inhibited NF- κB and STAT3 signaling pathways.