Monodisperse microspheres composed of thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) core and biocompatible porous ethyl cellulose (EC) shell embedded with PNIPAM gates have been successfully prepared by microfluidic emulsification, solvent evaporation and free radical polymerization. Attributing to the coating of EC shell, the mechanical strength and biocompatibility of the core-shell microsphere are much better than those of the PNIPAM core itself. Fourier transform infrared (FT-IR) spectrometer and scanning electron microscopy (SEM) are employed to examine chemical compositions and microstructures of prepared microparticles. By the cooperative action of EC shell with PNIPAM gates and PNIPAM core, the proposed core-shell microspheres exhibit satisfactory thermo-responsive controlled release behaviors of model drug molecules rhodamine B (Rd B) and VB12. At temperatures above the volume phase transition temperature (VPTT) of PNIPAM, the release rate of solute molecules is much faster than that at temperatures below the VPTT. The controlled factor of the prepared core-shell microspheres for VB12 release reaches to as high as 11.7. The proposed microspheres are highly attractive for controlled drug delivery. (C) 2012 Elsevier Inc. All rights reserved.