Retinal vascular inflammation is a common characteristic of diabetes. It is marked by upregulation of a major retinal endothelial cell adhesion molecule ICAM-1 that promotes leukocyte-endothelial adhesion. The adherent leukocytes subsequently release cytotoxic, hyperpermeability and pro-inflammatory factors to cause extensive vascular damage in the retina that often lead to diabetic retinopathy (DR), a vision-threatening condition that affects nearly 40% of all people with diabetes. Past studies have identified retinal endothelial ICAM-1 expression as a rate-limiting step in DR pathogenesis because inhibiting it blocked DR progression in vivo. A common anti-ICAM-1 therapy for DR involves the use of salicylates that block activation of NF-KB, a major transcription factor required for ICAM-1 upregulation. However, the clinically-used high levels of salicylates cause severe adverse off-target effects in the body. To address this major limitation, this

work describes the use of biomimetic nanoparticles (NPs) that selectively deliver salicylate to ICAM-1-expressing retinal endothelial cells (ECs) and blocks leukocyte-EC adhesion. Specifically, these biomimetic NPs are derived from red blood cell membranes, surface modified with an ICAM-1-targeting single chain variable fragment (scFv), and loaded with sodium salicylate. Detailed physicochemical characterization revealed that these NPs are ~16035 nm in diameter, successfully conjugate anti-ICAM-1 scFv on their surface, and exhibit ~45% drug incorporation. Importantly, in vitro studies show that these drug-loaded NPs undergo preferential (~2-fold greater) uptake in ICAM-1-expressing retinal ECs and, crucially, exhibit a remarkable 700-fold greater efficacy of sodium salicylate in blocking leukocyte-EC adhesion. These promising findings lay the foundation for more detailed assessment of this anti-inflammatory nanotherapeutic as a new and improved treatment strategy for DR.