Cyclosporine A (CyA) is a poorly soluble peptide and the available preparation is the surfactant based Sandimmum Neoral®. In this study, we developed a novel pH-sensitive nanomatrix system of CyA with medical-grade nanoporous silica and Eudragit® to enhance the oral absorption of CyA as well as to improve the potential nephrotoxicity caused by the pronounced initial plasma peak of Neoral®. The nanomatrixs were prepared by an absolutely simple conventional process. The scanning electron microscopy (SEM), X-ray powder diffraction analysis (XRD), differential thermal analysis (DSC) and specific surface area and pore size analysis were used to analyze the physicochemical characterization of the nanomatrix. The nanomatrix, consisted of CyA, Eudragit® S100 and Sylysia 350 (1/5/5, w/w/w %), not only increased the dissolution of CyA in vitro but also exhibited excellent enteric behavior. The characterization of CyA nanomatrix showed the CyA was highly dispersed in the nanomatrix in a molecular or amorphous state and partly filled into the nanopores of Sylysia 350. The results of comparative pharmacokinetic study showed that the optimized nanomatrix had a relative bioavailability of 90.8% with Neoral® but a lower Cmax than that of Neoral®. In conclusion, the novel nanomatrix of CyA, composed of pharmaceutical excipients of biological safety and easily prepared, is expected to become a promising marketed product for the oral delivery of CyA.