PROJECT SUMMARY Pneumonia is the most common cause of hospitalization due to infection in the US and the most common cause of infection-related death. Mortality in healthcare-associated pneumonia (HAP) is 13% overall and 36% in patients admitted to the ICU. Bacterial lung infections are also a frequent complication of prolonged mechanical ventilation required in patients after major surgery, traume, and severe lung injury due to viral pneumonias (e.g. SARS-Cov2); mortality in such ventilator-associated pneumonias (VAP) is even more grave. Two leading bacterial causes of HAP/VAP are the Gram-negative nosocomial pathogens Pseudomonas aeruginosa (PA) and Acinetobacter baumannii (AB), both frequently highly multidrug-resistant and can develop resistance to last line carbapenems. Gram-negative bacterial HAP/VAP is frequently complicated by neutrophil- and cytokine driven hyperinflammation and associated lung damage—which when severe is designated “acute respiratory distress syndrome” (ARDS). There are no standard clinically proven therapies to support the host immune system in clearing severe bacterial pneumonia while simultaneously suppressing the hyperinflammation that leads to lung tissue destruction. Here we describe a highly innovative drug concept for critically ill patients with severe PA and AB pneumonia with a unique multifold mechanism of action: biomimetic human macrophage membrane-coated nanoparticles (MΦ-NP). MΦ-NP are made by wrapping cell membranes derived from human macrophages around biodegradable polymeric cores, retaining their membrane lipid bilayer and full repertoire of surface structures and receptors, just on a nano (~1/50,000th) scale. The natural biomimicry imparts to the MΦ-NP the ability to bind, sequester and neutralize bacterial toxins, lipopolysaccharide (LPS), and host-derived proinflammatory cytokines, a tripartite mechanism of action to curb harmful inflammation, preserved tissue integrity, and facilitate bacterial clearance. Here we describe our extensive prior published and preliminary results that strongly support the novel therapeutic concept of MΦ-NP for the treatment of severe Gram- bacterial pneumonia in ICU patients, and how the proven team at San Diego-based Cellics Therapeutics will support our Clinical Development Plan at every step of the pathway toward an investigational new drug (IND) application and entry into Phase 1 clinical trials to meet this critical unmet medical need. In Aim 1 we will study the capacity of MΦ-NP to preserve lung epithelial and endothelial barrier integrity and function upon pneumonia challenge, including work in novel 3D human iPSC derived organoids. In Aim 2, we will examine the ability of MΦ-NP to block excessive alveolar macrophage and neutrophil-driven inflammation but preserve their antibacterial function against MDR Gram- pathogens. Finally in Aim 3, we will conduct in vivo analysis of the benefits of intratracheal (IT) and/or intravenous (IV) MΦ-NP therapy on mortality, ba...