Equip your vehicle for the right terrain: Using features of local pathology to guide engineering of targeted drug delivery systems

Drug delivery systems (DDS) have been engineered to target therapeutics to the primary site of disease for many varied pathologies. Lung disorders are especially advantaged, as the pulmonary endothelium's direct interface with the bloodstream makes it accessible and highly susceptible to injury. As such, the endothelium is damaged in many pathologies, characterized by dysregulation and structural and functional changes. Over the years, scientists have exploited these key features of endothelial dysfunction for targeted drug delivery. This review combines past and present research on DDS design directed toward the pathological pulmonary endothelium. Scientists have engineered DDS for endothelial delivery through the modification of nanocarrier size, shape, rigidity, and surface features, and the use of ligand-directed, biomimetic, stimuli-responsive, and physicochemical targeting strategies. While recent advances have brought these approaches closer to clinical relevance, challenges remain in their translation to therapeutic applications.