ABSTRACT / SUMMARY Acute critical illnesses rapidly lead to severe organ damage and loss of life. These illnesses include sepsis, stroke, and acute respiratory distress syndrome (ARDS). Here we focus on ARDS, which is acute inflammation of the lungs’ air sacs, and the cause of death in COVID-19. For ARDS and these other diseases, we have developed ligand-targeted nanocarriers that localize drugs to the inflamed microvasculature of affected organs. As we moved towards clinical translation, we found the key step is gaining control of complement, a set of plasma proteins that bind microbes and aid their clearance. But we found complement-nanoparticle interactions are a “double-edged sword”, with both benefits to optimize, and deleterious features to resolve. First, we found that complement protein C3 rapidly opsonizes particular nanoparticles, and that such C3- opsonized nanoparticles then act as “decoys” to ameliorate ARDS mouse models (e.g., nebulized LPS) by ~75%. The C3-coated nanoparticles accumulate in marginated leukocytes, which are key to ARDS pathophysiology, and cause those cells to leave the lungs. However, C3 opsonization induces an anaphylaxis-like reaction called CARPA (complement-activation-related pseudo-allergy). Therefore, in Aim 1, we will engineer nanoparticles that can function like C3-coated decoys to ameliorate ARDS, but without CARPA. We will also investigate the mechanism underlying nanoparticle decoy therapy. Then we will test the translational potential of these optimized decoy nanoparticles by testing them in fresh, perfused, ex vivo human lungs. Second, we found that the ligand-targeted nanoparticles we have been developing for drug delivery for years also induce CARPA. Therefore, in Aim 2, we will re-engineer our ligand-targeted nanoparticles to prevent CARPA. We will test a drug carrier we have previously used to concentrate drugs in the alveolar microvasculature of the lungs: liposomes conjugated to anti-PECAM antibodies that bind endothelial cells. We will test in vitro and in vivo in mice whether various engineered versions of anti-PECAM liposomes can evade C3 opsonization and CARPA, and thereby achieve more specific delivery to the lungs. Lastly, we will test these CARPA-avoiding nanoparticles with plasma from ARDS patients, as such patients have perturbed complement. Upon completion of these two Aims, we will have developed two technologies that may aid therapy of ARDS: 1) Decoy nanoparticles that safely cause marginated leukocytes to leave the lungs, and thereby ameliorate ARDS-like phenotypes; 2) A technology for preventing complement side effects such as CARPA when delivering ligand-targeted nanoparticles. As marginated leukocytes play pivotal roles in most acute critical illnesses, and CARPA sensitivity is common to those as well, the technologies developed here may impact not only ARDS, but also sepsis, stroke, and more.