Reduced Mortality in COVID‐19 Patients Treated With Inhaled Extracellular Vesicles Expressing CD24

BACKGROUND: Severe COVID-19, and other systemic infections, can trigger hyperinflammation leading to lung injury. EXO-CD24, an inhaled extracellular vesicle therapy with anti-inflammatory properties, has shown acute clinical benefit, but long-term effects on survival remain unknown. METHODS: We compared the mortality in 35 patients with moderate-to-severe COVID-19 treated with inhaled EXO-CD24 on five consecutive days in 2020, versus 105 matched controls receiving standard care (1:3 ratio). This 'real life' study was a retrospective follow-up extended to 4.6 years after infection, evaluating all-cause mortality as well as health-related quality of life in survivors (HRQoL). RESULTS: No deaths occurred in the EXO-CD24 group (0/35) versus 14 deaths (13.3%) among the matched controls (p < 0.05). The survival difference was most marked in the first month but persisted over time. At the end of the follow-up, theEXO-CD24 patients reported significantly better HRQoL, including well-being, physical function, and mobility. CONCLUSIONS: Repeated inhalations with EXO-CD24 is associated with improved survival and HRQoL up to 4.6 years post-treatment. These findings suggest durable benefits and support further evaluation of EXO-CD24 as an immunomodulatory therapy in severe inflammatory conditions. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04657497.