Stem Cell Membrane‐Coated Microribbon Scaffolds Induce Regenerative Innate and Adaptive Immune Responses in a Critical‐Size Cranial Bone Defect Model

Naturally‐derived cell membranes have shown great promise in functionalizing nanoparticles to enhance biointerfacing functions for drug delivery applications. However, its potential for functionalizing macroporous scaffolds to enhance tissue regeneration in vivo remains unexplored. Engineering scaffolds with immunomodulatory functions represents an exciting strategy for tissue regeneration but is largely limited to soft tissues. Critical‐sized bone defects cannot heal on their own, and the role of adaptive immune cells in scaffold‐mediated healing of cranial bone defects remains largely unknown. Here, mensenchymal stem cell membrane (MSCM)‐coated microribbon (µRB) scaffolds for treating critical size cranial bone defects via targeting immunomodulation are reported. Confocal imaging and proteomic analyses are used to confirm successful coating and characterize the compositions of cell membrane coating. It is demonstrated that MSCM coating promotes macrophage (Mφ) polarization toward regenerative phenotype, induces CD8+ T cell apoptosis, and enhances regulatory T cell differentiation in vitro and in vivo. When combined with a low dosage of BMP‐2, MSCM coating further accelerates bone regeneration and suppresses inflammation. These results establish cell membrane‐coated microribbon scaffolds as a promising strategy for treating critical size bone defects via immunomodulation. The platform may be broadly used with different cell membranes and scaffolds to enhance regeneration of multiple tissue types. Cell membrane coating represents a biomimetic strategy for modifying the surface of biomaterials. Coating macroporous microribbon scaffolds with mesenchymal stem cell membrane (MSCM) enhances cranial bone healing via immunomodulation. Primed MSCM‐coating contains ligands that promote Mφ polarization toward M2, induce Treg differentiation and TCD8+ apoptosis, and enhance MSC osteogenesis. MSCM coating synergizes with BMP‐2 to further accelerate bone regeneration while suppressing inflammation.