Advanced Review Functional protein–organic/inorganic hybrid nanomaterials Rui Wang, 1 Yifei Zhang, 1 Diannan Lu, 1 Jun Ge, 1∗ Zheng Liu 1∗ and Richard N. Zare 2∗ Nanotechnology offers immense opportunities for regulating and improving biological functions of proteins in vitro. Recent years have witnessed growing efforts to develop protein-incorporated hybrid nanostructured materials with potential applications in functional materials, enzymatic catalysis, drug delivery, and analytical sciences. In this review, recent advances in functional protein–organic/inorganic hybrid nanomaterials are discussed with an emphasis on the novel preparation methods, resulting nanostructures, and their potential applications in drug delivery and enzymatic catalysis. Future directions toward the rational design of these bionanomaterials are suggested.  2013 Wiley Periodicals, Inc. How to cite this article: WIREs Nanomed Nanobiotechnol 2013. doi: 10.1002/wnan.1210 INTRODUCTION N anomaterials with controllable chemical compo- sitions and structures, large surface-to-volume ratios, various surface properties, and functional- ities offer many opportunities for regulating the biological function of incorporated protein 1–5 with interesting potential applications in catalysis, 6–9 drug delivery, 10–13 and biosensors. 14–17 By far, immo- bilization of protein onto nanomaterials, chemical conjugation of protein with synthetic polymers, in situ crosslinking of protein with polymers, and self- assembly of protein with organic/inorganic compo- nents represent commonly used methods to prepare protein-incorporated hybrid bionanomaterials, as dis- cussed in a number of reviews. 1,9,18–22 The design and synthesis of such hybrid bionanomaterials remain a challenge in terms of tailoring the structures of the bionanomaterials in response to their applica- tions. This review focuses on the recent advances of the preparation methods and structures of functional protein–organic/inorganic hybrid nanomaterials with ∗ Correspondence to: zare@stanford.edu; liuzheng@mail.tsinghua. edu.cn; junge@mail.tsinghua.edu.cn 1 Department of Chemical Engineering, Tsinghua University, Beijing, China 2 Department of Chemistry, Stanford University, Stanford, CA, USA potential applications to biocatalysis and drug deliv- ery. These newly developed methods are grouped into categories in terms of protein–polymer conjugates, protein–polymer nanogels, and protein-incorporated complex hybrid nanomaterials. The design and syn- thesis of these materials for drug delivery and enzy- matic catalysis are also discussed with reference to the conventionally modified biological molecules. AN OVERVIEW OF THE PROTEIN-INCORPORATED HYBRID NANOMATERIALS As shown in Table 1, the preparation methods for protein–organic/inorganic hybrid nanomaterials developed to date can be grouped into four categories in terms of immobilization, conjugation, crosslinking, and self-assembly. Some typical nanostructures of the protein-incorporated nanomaterials are given in Figure 1. Immobilization is the most extensively used method, which gives reusable biocatalysts with enhanced stabilities of enzymes, as reviewed elsewhere. 22–24 Chemical conjugation and in situ crosslinking of proteins with polymers are effective for preparing protein–polymer hybrid structures with integrated properties of both proteins and synthetic polymers. As exemplified by PEGylation, the  2013 Wiley Periodicals, Inc.