ABSTRACT: Nanoscale scaffolds that characterize high bioactivity and the ability 11 to deliver biomolecules provide a 3D microenvironment that controls and stimulates 12 desired cellular responses and subsequent tissue reaction. Herein novel nanofibrous 13 hybrid scaffolds of polycaprolactone shelled with mesoporous silica (PCL@MS) 14 were developed. In this hybrid system, the silica shell provides an active biointerface, 15 while the 3D nanoscale fibrous structure provides cell-stimulating matrix cues 16 suitable for bone regeneration. The electrospun PCL nanofibers were coated with 17 MS at controlled thicknesses via a sol−gel approach. The MS shell improved surface 18 wettability and ionic reactions, involving substantial formation of bone-like mineral 19 apatite in body-simulated medium. The MS-layered hybrid nanofibers showed a 20 significant improvement in mechanical properties, in terms of both tensile strength 21 and elastic modulus, as well as in nanomechanical surface behavior, which is 22 favorable for hard tissue repair. Attachment, growth, and proliferation of rat 23 mesenchymal stem cells were significantly improved on the hybrid scaffolds, and their osteogenic differentiation and subsequent 24 mineralization were highly up-regulated by the hybrid scaffolds. Furthermore, the mesoporous surface of the hybrid scaffolds 25 enabled the loading of a series of bioactive molecules, including small drugs and proteins at high levels. The release of these 26 molecules was sustainable over a long-term period, indicating the capability of the hybrid scaffolds to deliver therapeutic 27 molecules. Taken together, the multifunctional hybrid nanofibrous scaffolds are considered to be promising therapeutic platforms 28 for stimulating stem cells and for the repair and regeneration of bone.