Abstract Biomarker-guided treatment is key to improve outcomes of many diseases. The current COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis due to lagged vaccination and inefficient control of the virus, which has caused over 253 million cases and more than 5.1 million deaths as of November 15, 2021. For potential new strains that may infect vulnerable populations or escape from vaccination-mediated prevention, biomarker-guided specific therapeutics against broad strains of SARS- CoV-2 as well as future corona viruses are still urgently required to prevent viral spreading and save human lives from severe COVID-19. In exploration of soluble components in the plasma of COVID-19 patients during acute infection and convalescent phase, we detected ACE2 expression in a subset of circulating exosomes and found that the levels of ACE2+ exosomes (exoACE2) are associated with severity of COVID-19. Purified ACE2+ exosomes competitively blocked the SARS-CoV-2 infection through inhibiting the viral Spike protein with its cellular receptor ACE2. We hypothesize that the exosomal ACE2 not only serves a biomarker for COVID-19 pathogenesis but also represents an innovative decoy therapy to treat all strains of coronaviruses that use ACE2 for viral entry. We propose two specific aims: (1) to establish a standard clinical assay for exoACE2 analysis; and (2) to develop exoACE2 therapeutics against the current and future broad strains of coronaviruses. Two academic institutions (Northwestern University and MD Anderson Cancer Center) will team up with the industry partner ExoMira Medicine for collaborative translation of exoACE2 into clinical applications, i.e. biomarker-guided therapy against SARS-CoV-2 and other coronaviruses.