Abstract Inflammation is well recognized as the underlying mechanism in a multitude of acute and chronic diseases, from injury to pain to cancer. This research proposes to design theranostic nanoemulsion-based agents that have capabilities for imaging by positron emission tomography (PET), near-infrared fluorescence (NIRF) optical and magnetic resonance imaging (MRI), and for treating inflammation. The theranostic nanoemulsions will target macrophages, as they simultaneously deliver a COX-2 inhibitor drug (celecoxib), positron emitting radionuclides and a NIRF dye. The core of the nanoemulsion is perfluorocarbon (PFC), which allows for 19F- MRI. The agents developed in this project will lead to broadly applicable treatment and diagnostic strategies for inflammation driven diseases. The PFC nanoemulsion platform (droplet size of 100-150 nm) incorporates hydrophobic small molecule drugs and has a lipid/PEG outer shell that can be readily modified with chelators for labeling with metal radionuclides such as 64Cu and 89Zr. We previously demonstrated that based on its size (120-140 nm) and surface properties, this nanoemulsion specifically targets macrophages and can deliver poorly soluble small molecule anti-inflammatory drugs (e.g. COX-2 inhibitor celecoxib) to sites of inflammation in rodent models. Preliminary data show these nanoemulsions reduce inflammation in mice while producing inflammation specific NIRF images of the drug-induced changes of macrophage trafficking in vivo. We hypothesize that addition of chelators for complexation of Cu-64 and Zr-89 for PET imaging will be highly translatable for human imaging to monitor drug delivery. The specific aims will focus on strategies for synthesis of chelators-nanoemulsion constructs that incorporate drugs and PET radionuclides and their characterization in vitro (Aim 1). PET imaging and biodistribution, as well as proof-of-principle validation of the nanoemulsion- mediated drug delivery and efficacy will be performed in a mouse model of inflammation (Aim 2). If successful, we will have a lead theranostic nanoemulsion for PET and drug delivery that can be further examined in models of cancer, pain and other disease states where inflammation plays a major role in morbidity, as part of a future R01 application.