Mesenchymal stem cells (MSCs) transplantation is an emerging and attractive therapy for immune dysregulation diseases like systemic lupus erythematosus (SLE). However, its application is hindered by short in vivo persistence and poor cellular survival after injection. Here, inspired by the native extracellular matrix (ECM) composition, we presented a novel peptide dendrimer-based microgel encapsulated with MSCs via a microfluidic approach for SLE treatment. By varying microfluidic parameters, monodisperse microgels with tunable diameters, porous microstructures, mechanical stiffness, and immune-isolation potential could be precisely achieved. As the water polymerization environment and ECM like components, the resultant microgels exhibited minimal toxicity in vivo and in vitro. We have also demonstrated that the MSCs encapsulated microgels could significantly increase the cellular bioactivity, enhance the immunomodulatory function, and attenuate disease symptoms in MRL/lpr mice. These results indicate the bioinspired microgels with MSCs encapsulation have potential clinical values in the treatment of SLE and other immune dysregulation diseases.