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However, due to the complex pathogenesis and cross\u2010interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood\u2013retinal barrier (BRB) injury can attenuate DR. For this, a glucose\u2010responsive hydrogel named Cu\u2010PEI\/siMyD88@GEMA\u2010Con A (CSGC) is developed that effectively delivers Cu\u2010PEI\/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu\u2010PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu\u2010PEI NPs decreases IL\u201018 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross\u2010interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.<\/jats:p>","DOI":"10.1002\/advs.202402368","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T15:19:19Z","timestamp":1718983159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A Glucose\u2010Responsive Hydrogel Inhibits Primary and Secondary BRB Injury for Retinal Microenvironment Remodeling in Diabetic Retinopathy"],"prefix":"10.1002","volume":"11","author":[{"given":"Yue","family":"Zhou","sequence":"first","affiliation":[{"name":"Tianjin Key Laboratory of Drug Delivery &amp; High\u2010Efficiency School of Pharmaceutical Science and Technology Tianjin University  Tianjin 300072 P. R. 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