Diabetic retinopathy (DR) is a common microvascular complication of diabetes necessitating early intervention to impede progression, despite current clinical treatments focusing on advanced stages. Essential oils from Fructus Alpiniae zerumbet (EOFAZ) have demonstrated efficacy in protecting against high glucose (HG)-induced Müller cell activation and DR development. This study introduced a reactive oxidative species (ROS)-responsive drug delivery system (NPSPHE@EOFAZ) targeting early DR stages and oxidative stress. Our engineered nanoparticles effectively deliver EOFAZ into HG-exposed Müller cells by detecting and responding to elevated oxidative stress levels. The NPSPHE@EOFAZ significantly inhibited abnormal cell growth, reduced oxidative stress, and alleviated inflammation in vitro. In vivo experiments on diabetic mice with DR revealed that NPSPHE@EOFAZ mitigated early pathological changes by reducing oxidative stress and inflammation while also alleviating organ damage in the heart, liver, spleen, lung, and kidney. These findings underscore the potential of NPSPHE@EOFAZ as a promising antioxidant for early intervention in DR pathogenesis.