PROJECT SUMMARY/ABSTRACT Bacterial pneumonia causes severe local inflammation in the lungs that can result in serious complications if left unchecked. While antibiotics are oftentimes an effective treatment, drug-resistant bacteria that do not respond to the standard of care represent a major threat. Bacteria contain a number of pathogen-associated molecular patterns that are highly efficient at activating the immune system, and the overproduction of proinflammatory factors can have deleterious effects such as causing the air sacs within the lungs to become filled with fluid. To address these negative effects, corticosteroids have been employed as an adjunct therapy in combination with antibiotic treatment. There is clinical evidence that supplemental anti-inflammatories can reduce patient morbidity and mortality, and the beneficial effects are the most pronounced in cases of severe disease. Despite their advantages, steroids are broadly immunosuppressive and cannot be administered at high dosages or over extended periods of time without side effects. In this proposal, our goal is to employ a genetic engineering approach for creating a next-generation a cellular nanoparticle (CNP) platform that can specifically target sites of inflammation. CNPs are an emerging class of nanocarrier that utilize the principles of biomimicry, and they have demonstrated considerable promise for drug delivery applications. Their fabrication involves the coating of synthetic nanoparticulate cores with naturally derived cellular membrane, which provides an inherently multifunctional and multi-antigenic layer of camouflage. We will further advance the CNP concept by genetically engineering the nanoparticles to express specific membrane-bound targeting proteins. Leveraging the fact that activated endothelial cells at sites of inflammation upregulate their expression of cell adhesion molecules, CNPs will be fabricated using cell membrane that has been engineered to express the cognate ligands. Each inflammation-targeting CNP formulation will be loaded with corticosteroids, delivering the payloads precisely to where they are most needed. By improving the therapeutic index of these drugs, we hope to prevent the harmful effects associated with excessive inflammation while reducing any treatment-related side effects. If successful, this approach could potentially be applied across a wide range of inflammation-driven pathologies.