Two pulmonary interfaces play the key role in respiratory infections, both bacterial and viral (e.g., COVID19). The invaders enter via external interface formed by airway and alveolar epithelial cells. The adjacent internal vascular interface formed by endothelial cells recruits and other host defense including neutrophils (PMN) to invasion site. Overzealous PMN hurt endothelium. Emerging reports implicate this collateral damage in COVID19 poor outcomes. Anti-inflammatory drugs could alleviate this issue, but pose risk of infection spread. To protect lungs from "friendly fire" without inhibiting PMN fighting infection we target nanocarriers loaded with anti-inflammatory agents using affinity ligands binding to specific epitopes on the pulmonary endothelium. Fortuitously, pilot screening of ~30 nanoparticles revealed that after IV injection some formulations lacking affinity ligands accumulate in the PMN in inflamed lungs. We want to use these findings for dual drug delivery to endothelium and adjacent PMN. In Aim 1, we will interrogate the nano-scale interface between the surface of PMN- tropic nanocarriers and microenvironment to elucidate the mechanism of PMN uptake. In Aim 2, we will investigate effect of endothelial- and PMN-tropic nanocarriers on the micro-scale interface of pulmonary microvasculature. These studies will elucidate the fundamental mechanisms by which nanocarrier material properties dictate opsonization, and in turn tropism for PMNs, the most important leukocyte in pneumonia. We will determine how nanocarriers localize to the two key cell types in defense against pneumonia, thus creating a platform drug delivery system to treat both bacterial and viral pneumonia.

Respiratory infections including COVID19 ignite the host response in the lungs. Endothelial cells in the pulmonary vasculature mediate recruitment of neutrophils to fight the invaders. Neutrophils inflict the collateral damage to endothelium. Emerging clinical reports implicate this complication in poor outcomes of COVID19 in the high-risk patients. We have devised nanocarriers for targeted delivery of protective agents to endothelium using ligand molecules with specific affinity to these cells. In the pilot studies we have also found that some nanocarriers lacking affinity ligands fortuitously accumulate on the neutrophils residing in the pulmonary vasculature. Using these two types of nanocarriers may permit cell-specific delivery of distinct drugs to endothelium vs neutrophils. Dual drug delivery of distinct pharmacological interventions in these adjacent cells may enable alleviation of the endothelial collateral damage concomitantly with desirable modulation of neutrophil activity. In this project, we will devise these dual drug delivery system(s), characterize their mechanism of action and appraise their benefit/risk ratio in pre-clinical translational studies in animal models of respiratory infection.