DNA‐Scaffolded Bispecific Antibodies Enhance Mesenchymal Stromal Cell Therapy for Inflammatory Bowel Disease

Abstract Mesenchymal stromal cells (MSCs) are considered a promising cell‐based therapy for inflammatory bowel disease (IBD), due to their potent immunomodulatory properties and robust regenerative potential. However, their therapeutic efficacy against IBD is hindered by poor homing capacity and excessive leukocyte infiltration at inflamed colonic sites. In this study, MSCs with a Y‐shaped bispecific antibody (YMV) assembled via DNA nanotechnology, which integrates anti‐vascular cell adhesion molecule‐1 (anti‐VCAM‐1) and anti‐mucosal addressing cell adhesion molecules‐1 (anti‐MAdCAM‐1) antibodies are engineered, to enhance targeted delivery and inhibit leukocyte recruitment. YMV‐modified MSCs show an approximately threefold enhancement in adhesion efficiency compared with native MSCs. Notably, they effectively compete for MAdCAM‐1 binding sites and significantly suppress leukocyte adhesion. In a mouse model of IBD, YMV‐MSCs demonstrate enhanced homing to the colon, promote mucosal repair, reduce leukocyte infiltration, and attenuate local inflammation. This DNA‐mediated bispecific antibody modification strategy improves MSCs targeting and exerts anti‐inflammatory effects by blocking leukocyte recruitment, offering a promising platform for MSC‐based therapy.