Ongoing extracellular matrix (ECM) mimics that dynamically adapt to cellular behaviors can more effectively regulate the fate of stem cells. In this study, a peptide nanofiber is developed by integrating integrin receptor-targeting peptides and heparan-sulfate proteoglycan-targeting peptides (KRSR) with self-assembling peptide fragments (FFF) to create ECM mimics. These nanofibers can dynamically self-assemble and co-assemble on the surface of bone marrow stem cells (BMSCs). Further investigations show that the co-assembly of these peptide nanofibers enhances cell proliferation and directs stem cell differentiation toward osteogenesis but not adipogenesis, thereby improving the quality of regenerated bone. We further explore the mechanisms of ECM mimics in regulating BMSCs’ differentiation through cell immunofluorescence staining and RNA sequencing analysis. The co-assembly of peptide nanofibers regulates BMSCs by interacting with cell membrane receptors, which triggers intracellular mechanotransduction and activates the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways. Consequently, a customized microenvironment is created to support BMSC functionality and tissue regeneration.

Graphical abstract