A sustained release system that composed of biodegradable core-sheath nanofibers in 3D hierarchy has been developed through electrospinning of water-inoil precursor emulsion, in which theophylline dissolved in water was labeled as 'aqueous phase' and PLA solution was considered as 'organic phase'. SEM images revealed that the fibers crossed and overlapped with each other, forming a 3D network-like structure. TEM indicated that the drug was well incorporated into PLA nanofibers, forming a core-sheath structure, which represented a reservoir-type delivery system. The fiber scaffolds were further characterized by FTIR, XRD, TGA, and DSC, which proved theophylline was successfully loaded into the fibers in an amorphous form. The release of drug consisted of three sequential stages, in which the release rate decreased successively. The changes on release rate were proved to be related to the drug diffusion and polymer degradation. At nearly 30 days, the drug still released continuously. This was accomplished by the gradually swelling and degradation of PLA. The successful preparation of the 3D core-sheath nanofibers can incorporate a water-soluble drug in a biodegradable polymer, which effectively protected the activity of the drug, inhibited a sudden release and accomplished sustained release.