ABSTRACT / SUMMARY Despite the advent of antibiotics and antivirals, pneumonia remains a major killer. In typical years, it kills >50,000 Americans, and in the last year, nearly 10x that amount due to COVID-19. The reason for these deaths is rarely because we cannot stop microbial expansion. Rather, it is due to the host response, in which local inflammation in the lungs causes a very high concentration of pro-inflammatory cytokines to spill into the blood, whereupon the cytokines travel to and damage remote organs. To eliminate excessive cytokines, many antibodies have been developed to bind and neutralize cytokines. However, these antibodies extravasate into the infected tissue (lungs), where they also inhibit the beneficial function of these cytokines, which is the orchestration of leukocytes to clear the microbes. To prevent this problem and the subsequent microbial overgrowth, there is a need to engineer therapeutics that only quench cytokines in the bloodstream, and not in the infected tissues that rely upon cytokines for microbial clearance. To accomplish this, we have developed RBC-Mops. RBC-Mops bind and quench cytokines, but only in the bloodstream, with no extravasation into infected tissues. We will build and test RBC-Mops across two Aims: In Aim 1, we will test RBC-Mops ability to bind their targets in vitro, evaluate for damage to RBCs themselves, and determine the pharmacokinetics and biodistribution of RBC-Mops in naive mice. In Aim 1, we will test RBC-Mops in the Klebsiella mouse model of pneumonia, evaluating benefits to the lungs and remote organs, while also investigating potential side effects. This R21 is designed to produce and validate the prototype RBC-Mop within 2 years. After that, we will apply for an R01 to further the translational potential of RBC-Mops and better understand their mechanisms. Eventually, we hope to develop a combination of RBC-Mops that can eliminate cytokines and other circulating toxins, to ameliorate a large range of acute illnesses, including viral pneumonia (COVID-19), sepsis, and sterile cytokine release syndromes produced by immunological therapies.