Stem cells with their intrinsic ability to differentiate to specific cell types have been clinically used as the most promising cell therapy. However, the injection-based administration in most clinical trials shows cell retention rates as low as 1% within days of transplantation. Herein, core-shell nanofibers of PLCL (Poly(lactide-co-ε-caprolactone)) and Gelatin-Methacrylate (Gel-MA), respectively, were fabricated to support the 3D delivery of human mesenchymal stem cells (hMSCs). The core-shell ratios can be accurately controlled using coaxial electrospinning, achieving smooth sliding fibers with up to 85 wt% of Gel-MA shell. Different core-shell flow rate ratios were systematically investigated. Either an increase of the concentration of the core PLCL solution or an increase of core solution flow rate can lead to an increase of the fiber diameter from 0.26 μm to 1.38 μm, and a decrease of numbers of beads from 33 per 100 fibers to bead-free. Significantly enhanced hMSCs proliferation (~2 folds over 7 days) on the three dimensional (3D) core-shell fibers were observed compared to that on 2D culture. Moreover, hMSCs cellularized 3D core-shell fibers can be directly injected as 4 cm² meshes through a catheter, with an 80% viable retention after injection, indicating their great promise in advancing stem cell therapy by both improving viable retention and meanwhile allowing minimally invasive administration.