PD‐L1‐Expressing Mesenchymal Stem Cells for Autoimmune Diseases: From Avidity‐Based Microfluidic Enrichment to Enhanced Immunoregulation

Mesenchymal stem cell (MSC) therapy has emerged as an effective strategy for immune‐mediated disorders by modulating immune activation and inflammatory responses; however, clinical translation remains limited by intrinsic cellular heterogeneity and inconsistent immunoregulatory potency. Here, we present an avidity‐based microfluidic sorting platform for high‐sensitivity enrichment of MSCs with elevated programmed death‐ligand 1 expression (PD‐L1 High MSCs) via dendrimer‐mediated multivalent interactions. The platform utilizes surface‐immobilized dendrimer–peptide conjugates, in which poly(amidoamine) dendrimers function as multivalent scaffolds that amplify individual peptide–receptor interactions into strong overall avidity, yielding enhanced PD‐L1 binding kinetics compared with conventional antibodies. When integrated into a microfluidic system, this avidity interface enables selective capture of PD‐L1 High MSCs under controlled shear stress, followed by mild proteolytic dissociation for gentle recovery while preserving cell viability and proliferative capacity. Functionally, enriched PD‐L1 High MSCs exhibit enhanced immunosuppressive activity, characterized by reduced secretion of TNF‐ α and IFN‐ γ , reflecting effective suppression of immune effector cell activation and resulting in protection of normal epithelial cells in coculture assays. Compared with fluorescence‐activated cell sorting, this platform achieves superior functional enrichment without antibody labeling or loss of cell functionality. Collectively, this study establishes an avidity‐based microfluidic strategy to mitigate MSC heterogeneity and enable scalable production of immunoregulatory MSCs.