Project Summary Pneumonia is the leading infectious cause of death in the United States each year, and is responsible globally for over 1 million neonatal deaths. As a result of the significant morbidity and mortality, improving treatment options for bacterial pneumonia would have a substantial impact on public health. The antibiotic choices available to treat pneumonia have been largely unchanged over the past several decades. At the same time, the number of antibiotic resistant infections has been increasing steadily. The difficulty with improving treatment lies with three major problems related to drug delivery: 1) inhaled antimicrobials cannot reach alveoli blocked by purulent material rendering them inefficient; 2) pneumonia patients are frequently septic, which makes them less likely to tolerate the off-target effects of antibiotics; 3) antibiotic resistance is growing at an alarming pace. We aim to solve these problems by developing a new antibiotic delivery system that combines nanotechnology and cell therapy: utilizing nano-scale carriers to deliver high antimicrobial concentrations directly to the site of infection via neutrophils. We have previously targeted nanocarriers to the lungs by a variety of means, including endothelium- targeting moieties; however, in this proposal we aim to target pulmonary intravascular neutrophils to create a treatment for bacterial pneumonia with our neutrophil-avid nanocarriers (NANs). The scientific objective of this proposal is to integrate our expertise in the innate immune system, cell therapy, and nanotechnology to develop a new paradigm for treating pneumonia, and eventually other infections. We hypothesize that NANs can deliver antibiotics to the proper compartments in the activated neutrophils and lungs to increase the potency of the cargo antibiotic. The aims are thus: 1) Determine the mechanism of interaction between NANs and neutrophils in vitro. 2) Assess directed-antibiotic delivery by NANs. The proposal’s other key objective is to train the candidate in innate immunity and nanomedicine drug delivery. This will comprise coursework, individualized mentoring, and hands-on training in tools such as nanocarrier production, analytical chemistry, and animal models of pneumonia.