The core-shell polymeric nanofiber, owing to its better controlled release of embedded or encapsulated drugs in contrast with the single-compartment nanofibers, has been extensively studied for biomedical applications such as tissue engineering and wound healing. Electrospinning with co-axial needles is the dominant technique to fabricate nanofiber mat, however, associated with potential limitations such as high voltage requirement, costly equipment, slow deposition rate, required trained personal, not suitable in situ fabrication, and direct deposition of core-shell nanofibers on the wound at patient bedside. To address the above limitations, the work aims to introduce a novel co-axial airbrushing method to fabricate core-shell nanofibers using a simple setup and low-cost equipment, yet having a unique ability for fabrication at patient bedside and direct deposition on wound bed. Air-brush with a coaxial needle is designed to flow two different polymers solution with model biomolecules through core [PEO (polyethylene oxide)/poly-dl-lactide/PCL (polycaprolactone)] and shell (PCL/PEO) needle for the fabrication of the model core-shell nanofiber. Various processing parameters such as flow rate, air pressure, working distance, and concentration of polymer solution which affect the morphology of core-shell nanofibers were studied and found to have a prominent effect. The PCL-PEO nanofiber possesses a defined shell and core structure, tunable sustained release behavior of model proteins (bovine serum albumin and basic fibroblast growth factor; bFGF), and improved mechanical strength. In vitro interaction of human bone marrow-derived mesenchymal stem cells with core-shell fibers demonstrated the cytocompatibility and proliferative and differentiative (for bFGF loaded) properties of the core-shell nanofiber mat. Co-axial airbrushing can be used as a superior less-expensive technique for the fabrication of biomolecules/drug encapsulated core-shell fibers scaffold at patient bedside, which can mimic complex in vivo environment and could modulate cells behavior close to their in vivo condition for tissue regeneration and wound healing. © 2018 American Chemical Society.