TARGETED THERAPEUTIC DELIVERY TO DISEASED LUNGS USING ENUCLEATED MESENCHYMAL STEM CELLS - THERE IS CRITICAL NEED FOR CELL-BASED THERAPEUTICS THAT CAN BE ADMINISTERED INTRAVENOUSLY (IV), AND EFFECTIVELY HOME TO AND DELIVER THERAPEUTICS TO THE RESPIRATORY SYSTEM, WHILE MAINTAINING PATIENT SAFETY. CYTONUS THERAPEUTICS AND UC SAN DIEGO'S MEDICAL CENTER ARE CO-DEVELOPING ENUCLEATED MESENCHYMAL STEM CELLS WITH POTENTIAL TO DELIVER A WIDE RANGE OF BIOLOGICS TO TREAT RESPIRATORY DISEASES INCLUDING ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS). OUR NOVEL PLATFORM FOR THERAPEUTIC DELIVERY IS TO GENETICALLY ENGINEER MESENCHYMAL STEM CELLS (MSCS) WITH INFLAMMATION HOMING PROTEINS AND THEN GENTLY REMOVE THE NUCLEUS, THEREBY PROVIDING A HIGHLY UNIQUE, VIABLE, AND SAFE CELL THERAPEUTIC (CARGOCYTESTM) WITH SUBSTANTIAL LUNG HOMING POTENTIAL. ENUCLEATION GRANTS THE ABILITY TO GENETICALLY ENGINEER CARGOCYTES WITH MULTIPLE LUNG TARGETING MOIETIES AND A WIDE RANGE OF BIOLOGICAL PAYLOADS, WHILE MAINTAINING A CLINICALLY RELEVANT SAFETY PROFILE. OUR LUNG TARGETING STRATEGY IS BUILT ON THE KEY POTENTIAL OF CARGOCYTE THERAPEUTICS TO PERFORM ACTIVE-TARGETED DELIVERY TO THE LUNGS VIA AN INTRAVENOUS ROUTE (I.V.). NUCLEATED MSCS WILL FIRST BE EXTENSIVELY ENGINEERED WITH ESTABLISHED CHEMOATTRACTANT RECEPTORS CXCR4/CCR2 AND INFLAMED ENDOTHELIAL ADHESION MOLECULE PSGL-1 AND THEN ENUCLEATED PRIOR TO I.V. ADMINISTRATION. PROOF-OF-CONCEPT PRECLINICAL STUDIES WILL THEN BE PERFORMED TO DETERMINE WHETHER CARGOCYTES ENGINEERED WITH LUNG TROPHIC MOLECULES HOME TO INFLAMED LUNGS IN A CLINICALLY RELEVANT MURINE MODEL OF ARDS. THEREFORE, AIM 1 STUDIES WILL DETERMINE IF CARGOCYTES ENGINEERED WITH CCXCR4/CCR2 AND PSGL-1 HOME TO INFLAMED LUNG TISSUES AND AIM 2 STUDIES WILL DETERMINE IF CARGOCYTES EXIT THE VASCULATURE AND MOVE INTO THE INFLAMED/DAMAGED LUNG PARENCHYMA. IF CARGOCYTES HOME TO INFLAMED LUNG TISSUES AND EXIT THE VASCULATURE, IT COULD PROVIDE AN EFFECTIVE MEANS TO TREAT A WIDE RANGE OF RESPIRATORY DISEASES.