We developed a novel biocompatible material in the form of core-sheath nanofibers using coaxial electrospinning with tetracycline hydrochloride (TCH) as the model drug. To prepare nanofibrous membranes, poly(vinyl alcohol)-stilbazole quaternized (PVA-SbQ) and zein were first dissolved in acetic acid as the sheath form while drug TCH as the core form. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images demonstrated that the nanofibers had a round and smooth surface morphology with an average diameter of 980 +/- 252 nm. It showed distinct core-sheath structure at the sheath-to-core flow rate ratios of 1 and 0.5, respectively. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results revealed that the tetracycline hydrochloride was well distributed in the PVA-SbQ/zein matrix in an amorphous state. Fourier transform infrared spectroscopy (FTIR) analysis was used to verify the second-order interactions of the components, which revealed good compatibility of the components of the nanofibers. Thermal gravimetric (TG) analysis demonstrated that the core-sheath nanofibers improved the thermal stability of TCH. The nanofibers showed good cytocompatibility toward L929 cells, further confirming their potential use as drug delivery and wound dressing. In vitro drug release studies indicated that the core-sheath nanofibers exerted sustained release instead of initial burst release effect, and also followed the Fickian diffusion mechanism. The present study shows a simple but promising approach for the fabrication of novel biomaterials with structural characteristics for drug release profiles using coaxial electrospinning.