Plant-derived cellulose scaffolds constitute a highly viable and interesting biomaterial. They retain a high flexibility in shape and structure, present the ability to tune surface biochemistry, display a high degree of biocompatibility, exhibit vascularization, and are widely available and easily produced. What is also immediately clear is that pre-existing cellulose structures in plants can also provide candidates for specific tissue engineering applications. Here, we report a new preparation and fabrication approach for producing large scale scaffolds with customizable macroscopic structures that support cell attachment and invasion both in vitro and in vivo. This new fabrication method significantly improves cell attachment compared to that in our previous work. Moreover, the materials remain highly biocompatible and retain vascularization properties in vivo. We present proof-of-concept studies that demonstrate how hydrogels can be temporarily or permanently cast onto the macroscopic scaffolds to create composite plant-derived cellulose biomaterials. This inverse molding approach allows us to provide temporary or permanent biochemical cues to invading cells in vitro. The development of a new-generation of rapidly and efficiently produced composite plant-derived biomaterials provides an important proof that such biomaterials have the potential for numerous applications in tissue engineering.