This study investigates the development of a novel core–shell nanostructure for sustained drug release, focusing on the reverse gradient distribution of resveratrol (RES) and cellulose acetate (CA). The core–shell nanostructures were fabricated using coaxial electrospinning, a technique that allows for the creation of complex nanostructures with precise control over the spatial distribution of components. The core–shell nanofibers exhibited linear morphologies without beads or spindles, and the core–shell structure was confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analyses indicated that the components were highly compatible and presented in an amorphous state. In vitro dissolution tests demonstrated that the core–shell nanofibers effectively prevented initial burst release, extended the continuous-release time period, and reduced tailing-off release, resulting in a better sustained-release profile compared to traditional blended drug-loaded nanofibers. The mechanism underlying the improved sustained-release behavior was proposed, highlighting the importance of the reverse gradient distribution of RES and CA within the core–shell structure. This study provides a proof-of-concept for the development of advanced functional nanomaterials with gradient distributions of functional molecules within electrospun multi-chamber nanostructures.This study investigates the development of a novel core–shell nanostructure for sustained drug release, focusing on the reverse gradient distribution of resveratrol (RES) and cellulose acetate (CA). The core–shell nanostructures were fabricated using coaxial electrospinning, a technique that allows for the creation of complex nanostructures with precise control over the spatial distribution of components. The core–shell nanofibers exhibited linear morphologies without beads or spindles, and the core–shell structure was confirmed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR) analyses indicated that the components were highly compatible and presented in an amorphous state. In vitro dissolution tests demonstrated that the core–shell nanofibers effectively prevented initial burst release, extended the continuous-release time period, and reduced tailing-off release, resulting in a better sustained-release profile compared to traditional blended drug-loaded nanofibers. The mechanism underlying the improved sustained-release behavior was proposed, highlighting the importance of the reverse gradient distribution of RES and CA within the core–shell structure. This study provides a proof-of-concept for the development of advanced functional nanomaterials with gradient distributions of functional molecules within electrospun multi-chamber nanostructures.