Innate Immune‐Cloaked Microgel‐Coated Mesenchymal Stromal Cells Reverse Persistent Pulmonary Fibrosis via Reparative Macrophages

Abstract

Abstract The innate immune system plays a dual role in both mediating pathogenic processes following tissue damage and acting as a barrier to effective therapeutic delivery. Strategies that evade immune clearance while modulating host immune components offer promising solutions for treating complex chronic diseases, such as fibrosis. Here, an innate immune checkpoint material‐based strategy is presented in which mesenchymal stromal cells, coated with a soft conformal microgel and functionalized with the CD47 self‐marker agonist, effectively evade clearance by tissue resident macrophages. These engineered cells reverse persistent fibrotic damage in the lungs through a paracrine mechanism. Single‐cell RNA sequencing identifies a transitional antigen‐presenting macrophage subpopulation that mediates these reparative effects. By combining immune cloaking with the presentation of local signals encoded in the gel coatings, this strategy can be used to design secretory cells for long‐term tissue remodeling, enabling a living pharmacy for chronic tissue damage.