Developing biologically mimetic nanofibers (NFs) is crucial for their applications as scaffolds in tissue engineering and drug carriers. Herein, we present a strategy to facilely fabricate core-sheath NFs using coaxial electrospinning technique. Poly(epsilon-caprolactone) (PCL) and silk fibroin (SF) were employed as component materials to construct PCL/SF NFs with PCL cores uniformly encapsulated by SF sheaths. Scanning electron microscopy and transmission electron microscopy demonstrate a uniform core-sheath structure of the coaxial NFs. The engineered core-sheath structure confers the composite NFs with greatly improved properties including surface hydrophilicity and mechanical properties. In vitro cell culture validates that the core-sheath NFs are favorable to the cultured rat pheochromocytoma cells (PC 12) attachment. To further demonstrate the advantage of the coupled structural integrity, the PCL/SF core-sheath NFs were compared with the NFs produced from PCL and SF blend. Results showed that the PCL/SF NFs possessed a tensile strength of similar to 6.93 +/- 0.52 MPa and an elongation at break of similar to 294.31 +/- 24.17%, whereas the blend NFs possessed similar to 5.55 +/- 0.50 MPa and similar to 88.05 +/- 13.98%, respectively. Dexamethasone-phosphate sodium (DEX) was employed as a model drug, whereby the in vitro release study indicates that the NFs exhibit an ideal releasing profile, capable of releasing DEX continuously over a period of 450 h. The constructed PCL/SF core-sheath NFs are promising candidates for biomedical applications. POLYM. ENG. SCI., 2020. (c) 2020 Society of Plastics Engineers