Breath testing is a non-invasive and rapid diagnostic tool that is underutilized in the clinic due to scarcity of known breath biomarkers. Thousands of volatile organic compounds (VOCs) are excreted from the body in breath after having been produced endogenously as volatile metabolites or introduced exogenously via diet or environmental exposure. However, efforts to identify disease-specific VOCs have been hindered by technological and statistical limitations with currently-used -omic approaches. As an alternative approach to biomarker discovery, my lab has developed a diagnostic platform that leverages aberrant enzymatic activity during disease to engineer synthetic breath biomarkers. This platform technology consists of nanoparticle sensors that are delivered in vivo and release bio-orthogonal VOC reporters upon activation by targeted enzymatic activity. VOC trafficking pathways from tissues to breath offers a mechanism by which we can engineer exhaled biomarkers for diseases of different organ systems. In my talk, I will discuss how we designed and validated our volatile-releasing nanosensors for use in respiratory disease and future applications in gastrointestinal disease.