Airway Delivery of Encapsulated Cytokine-Secreting Cells for Local Immunomodulation in Inflammatory Lung Diseases

Dysregulated lung immunity drives excessive inflammation, leading to diseases like acute respiratory distress syndrome (ARDS) and pulmonary fibrosis that have high morbidity and mortality. Immunomodulation can attenuate inflammation and improve outcomes, however off-target effects from systemic delivery lead to adverse events that limit clinical translation. Herein, we develop a modular cell-based microcapsule platform that can be administered via the airway for localized, durable, and tunable delivery of various immunomodulatory proteins to the lungs. With this system, we demonstrate therapeutic efficacy of localized delivery of two proteins, interleukin-10 (IL-10) and interleukin-1 receptor antagonist (IL-1Ra), in a lipopolysaccharide-induced rodent model of ARDS. Single-cell RNA sequencing revealed that IL-10-secreting capsules reprogram the lung immune landscape in ARDS by altering myeloid cell composition, suppressing pro-inflammatory gene expression, and promoting the resolution of inflammation. In a bleomycin pulmonary fibrosis model, the platform enables durable and sustained delivery of IL-10 to alleviate hypoxemia and rescue lung architecture. Safety and biocompatibility were further confirmed in a large animal model, highlighting the clinical potential of the platform for the treatment of inflammatory lung diseases.