Electrospun nanofibrous scaffolds are highly recognized in tissue engineering since they can mimic the structure of extracellular matrix (ECM). However, the nanofibers fail to resemble the three dimensional geometry of organs, and the surface nanotopography of collagen fibrils in ECM. In order to mimic the structure of ECM in both macroscale (3D geometry) and microscale (surface nanotopography), an ingenious approach was developed in this study. Electrospun nanofibers collected in ethanol bath was soaked in CO2 saturated ethanol and subsequently foamed in a water bath, due to the escaping of CO2 gas. This simple green method takes the advantage of solubility difference of carbon dioxide (CO2 ) in ethanol and water, and is applicable to different materials. The foamed fluffy polycaprolactone (PCL) nanofibrous scaffolds achieved a low bulk density of 0.041 g/cm(3) and a high porosity of 95.3%. To resemble the surface nanotopography of ECM, shish-kebab structure was introduced onto the fluffy PCL nanofibers by controlled crystallization. The shish-kebab structures greatly enhanced the surface area of scaffolds from 6.9 m(2)/g for 2D PCL to 10.9 m(2)/g for 3D SK-PCL. In addition, 3T3 fibroblast cell culture results confirmed that the cells interacted strongly with the 3D fluffy nanofibers and migrated into the inner area of the scaffolds rapidly. Moreover, human fibroblast cell culture results confirmed further enhancement in cell attachment and proliferation on the fluffy shish-kebab structured nanofibrous scaffolds, which indicates the developed biomimetic 3D scaffolds have high potential to be used for 3D tissue regeneration.