Background/aim Icariin (ICA)-loaded zein/PLGA nanofiber membrane combined with MSCs was prepared by coaxial electrospinning and bioelectrospraying. Materials and methods SEM and TEM were used to evaluate the surface morphology and microstructure of the fiber membrane. Ultraviolet spectrophotometry was used to detect drug release. A LIVE/DEAD Viability/Cytotoxicity Kit and fluorescence staining were used to detect cell morphology and activity. Alkaline phosphatase and calcium mineralization deposition were used to evaluate the osteoinductive activity of the scaffold. Dynamic mechanical analysis was used to determine the Young’s modulus, maximum load, and maximum elongation of the prepared scaffold. Western blot was used to detect the related protein expression in MSCs induced by drug-loaded scaffolds. Results Good mechanical properties and stability were observed in the prepared drug-loaded scaffolds. SEM showed that there were a considerable number of MSCs dispersed in the scaffold. MSCs were evenly distributed, could grow evenly between fibers, and were arranged orderly along the fibers. Sustained release of ICA confers cell laden scaffold higher ALP activity and ECM mineral deposition through Runx2, OPN and OCN pathways. Conclusion Isotropic sustained release of ICA grant cell laden scaffolds rapid bone regeneration compacity which can provide a good osteogenic environment for loaded MSCs.