Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer due to both late diagnosis, and a lack of improvements over first line therapies. However, treatments can be advanced by actively targeting therapies to the tumor microenvironment. Based on tumor micro-environment modeling, enzyme and nanoparticle engineering is proposed to target PDAC desmoplasia (fibrous tissue thickening) and acidosis. Targeting improvements and efficacy will be screened in a dynamic in vitro platform. The developed platform can be adapted to screen the metabolic targeting efficiency of other smart therapies, and the delivery system is broadly applicable to tumors with metabolic or extracellular matrix abnormalities.