Abstract: Inflammation is the immune response to eliminate invading pathogens to prevent tissue injury, but excessive vascular inflammation is the pathogenesis of most diseases. Targeting inflammation pathways in vasculature may be an attractive means to manage the host immune responses for prevention of disease developments. In this proposal, we choose the mouse lung disease as a model to examine our hypothesis. Bacterial infection causes acute lung inflammation/injury (ALI) that quickly precipitates acute respiratory distress syndrome (ARDS). Current therapies are lung-protection ventilation and fluid-conservative management. There is no formally recommended pharmacological therapy for ALI/ARDS. Despite advances in care devices and efforts to develop new therapeutics, the mortality is still unacceptably high at 40%. In pathogenesis of ALI/ARDS, vascular inflammation promotes neutrophil adhesion and transmigration into the lungs. Neutrophils, a type of blood circulating leukocytes, bind and adhere to activated lung endothelium via several binding molecules between a neutrophil and an endothelium. Inspired by this unique intercellular interaction we have created nanovesicles made from the neutrophil membrane. We propose that neutrophil nanovesicles are a new drug delivery platform for delivering drugs to inflamed mouse lungs to control ALI developments. Based on our preliminary results on neutrophil nanovesicle production, intravital microscopy and LPS- or bacterium-induced acute lung injury mouse models, we have demonstrated the feasibility of this proposal, novel concepts and a great impact in nanomedicine. We propose three aims to test our hypothesis: Aim 1: To determine the properties of human neutrophil membrane formed nanovesicles required for endothelial targeting. Aim 2: Active loading of NF-κB inhibitors inside nanovesicles for improved therapies of mouse ALI induced by LPS. Aim 3: Co-delivery of an antibiotic and an anti-inflammation drug by nanovesicles enhances bacterial killing and resolves host inflammation in a bacterium-induced ALI mouse model. Completion of this proposal may lead to not only the development of a new delivery system but also shift the current paradigm in nanomedicine to biology-inspired design of nanotherapeutics.

Project Narrative: New drug delivery platforms require high drug loading, tissue specific targeting and their biosafety for dosing. Here, we propose a novel drug system made from neutrophil membrane-formed nanovesicles which can selectively target inflamed mouse lung endothelium, thus mitigating acute lung inflammation/injury (ALI). Completion of this proposal may lead to new therapies to ALI using cell membrane-formed nanovesicles.