Cold atmospheric plasma is a promising strategy for treating diabetic retinopathy.

Diabetic retinopathy (DR), a vision-threatening condition spanning non-proliferative and proliferative stages, faces efficacy and safety limitations with current standard care, demanding innovative solutions. We delineate hyperglycemia as the primary driver of DR pathogenesis via sustained oxidative stress, and hypoxia as the critical trigger for PDR transition through neovascularization, with AMP-activated protein kinase and hypoxia-inducible factor serving as key energy and oxygen sensors demarcating disease stages amid chronic inflammation. Supported by preclinical and clinical evidence, we propose cold atmospheric plasma (CAP), a multimodal source of reactive oxygen and nitrogen species, as a stage-specific adjuvant therapy for treating DR, given its good safety profile and multimodal regulatory capacities on antioxidant defenses, abnormal angiogenesis, and chronic inflammation that address core DR pathobiology. We emphasize the criticality of controlled CAP dosing for treating DR and proposed its differential calibrations for DR of different stages. This paper outlines a translational roadmap to overcome current treatment constraints that may transform DR management paradigms.