Biomolecular Engineering for Nanobio/Bionanotechnology

Nagamune Nano Convergence (2017) 4:9 DOI 10.1186/s40580-017-0103-4 REVIEW Open Access Biomolecular engineering for nanobio/ bionanotechnology Teruyuki Nagamune* Abstract Biomolecular engineering can be used to purposefully manipulate biomolecules, such as peptides, proteins, nucleic acids and lipids, within the framework of the relations among their structures, functions and properties, as well as their applicability to such areas as developing novel biomaterials, biosensing, bioimaging, and clinical diagnostics and therapeutics. Nanotechnology can also be used to design and tune the sizes, shapes, properties and functionality of nanomaterials. As such, there are considerable overlaps between nanotechnology and biomolecular engineering, in that both are concerned with the structure and behavior of materials on the nanometer scale or smaller. Therefore, in combination with nanotechnology, biomolecular engineering is expected to open up new felds of nanobio/ bionanotechnology and to contribute to the development of novel nanobiomaterials, nanobiodevices and nanobiosystems. This review highlights recent studies using engineered biological molecules (e.g., oligonucleotides, peptides, proteins, enzymes, polysaccharides, lipids, biological cofactors and ligands) combined with functional nanomaterials in nanobio/bionanotechnology applications, including therapeutics, diagnostics, biosensing, bioanalysis and biocatalysts. Furthermore, this review focuses on fve areas of recent advances in biomolecular engineering: (a) nucleic acid engineering, (b) gene engineering, (c) protein engineering, (d) chemical and enzymatic conjugation technologies, and (e) linker engineering. Precisely engineered nanobiomaterials, nanobiodevices and nanobiosystems are antici- pated to emerge as next-generation platforms for bioelectronics, biosensors, biocatalysts, molecular imaging modali- ties, biological actuators, and biomedical applications. Keywords: Engineered biological molecules, Therapy, Diagnosis, Biosensing, Bioanalysis, Biocatalyst, Nucleic acid engineering, Gene engineering, Protein engineering, Conjugation technologies 1 Introduction Nanobiotechnology is used in relation to the ways Nanotechnology is the creation and utilization of mate- in which nanotechnology is used to create materials, rials, devices, and systems through controlling matter devices and systems for studying biological systems and on the nanometer scale, and it is the key technology of developing new biological assay, diagnostic, therapeutic, the twenty-frst century. Te ability to exploit the struc- information storage and computing systems, among oth- tures, functions and processes of biological molecules, ers. Tese systems use nanotechnology to advance the complexes and nanosystems to produce novel functional goals of biological felds. Some nanobiotechnologies scale nanostructured biological materials has created the from the top down, such as from microfuidics to nano- rapidly growing felds of nanobiotechnology and bion- fuidic biochips (e.g., lab-on-a-chip for continuous-fow anotechnology, which are fusion research felds of nano- separation and the detection of such macromolecules technology and biotechnology [1]. Although these words as DNA and proteins [2], point-of-care biosensors for are often used interchangeably, in this review, they are detecting biomarkers and clinical diagnosis [3–7], and utilized in terminologically diferent ways, as follows. solid-state nanopore sensors for DNA sequencing [8]). Other nanobiotechnologies scale from the bottom up for the fabrication of nanoscale hybrid materials, such as *Correspondence: [email protected]‑tokyo.ac.jp Department of Chemistry and Biotechnology, Graduate School complexes consisting of nanoparticles (NPs) (e.g., mag- of Engineering, The University of Tokyo, Tokyo, Japan netic NPs, AuNPs and AgNPs, silica NPs, quantum dots © Korea Nano Technology Research Society 2017. This article is distributed under the terms of the Creative Commons Attribu- tion 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Nagamune Nano Convergence (2017) 4:9 Page 2 of 56 (QDs), polymeric micelles, liposomes, dendrimers, and 2 Application of engineered biological molecules fullerenes) and biological molecules, which are highly to nanobio/bionanotechnology useful for biosensing, bioimaging, diagnostic and thera- Nanobio/bionanotechnology has created new opportuni- peutic applications in healthcare [9–15]. ties for advances in diverse felds, including life science, On the other hand, bionanotechnology refers to the medicine, electronics, engineering, and biotechnology. ways in which biotechnology is used to improve exist- Nanoscale materials [e.g., NPs, nanowires, nanofbers, ing or create new nanotechnologies through the study and nanotubes (NTs)] combined with various engineered of how biological systems work and the applications biological molecules (e.g., proteins, enzymes, oligonu- of biological molecules and systems to nanotechnol- cleotides, polysaccharides, lipids, biological cofactors and ogy. DNA and RNA nanotechnologies, the utiliza- ligands) have been explored in many biological application of the base-pairing and molecular self-assembly tions (e.g., therapy, diagnosis, bioimaging, biosensing, properties of nucleic acids to create useful materials, bioanalysis, biocatalysis, cell and organ chips, bioelec- such as DNA origami, DNA nanomachines, DNA scaf- tronic devices, and biological separation) (Fig. 1). Teir folds for electronics, photonics and protein arrays, and novel and unique properties and functions, such as high DNA and RNA aptamers, ribozymes and riboswitches, volume-to-surface ratio, improved solubility, quantum are important examples of bionanotechnology [16, size, macroscopic quantum tunnel and multifunctional- 17]. Another important area of research involves tak- ity, result in nanobiomaterials that are drastically difer- ing advantage of the self-assembly properties of pep- ent from their corresponding bulk materials. tides, proteins and lipids to generate well-defned 3D Te current review is focused on advances in the devel- structures, functional protein complexes, nanoflms opment of nanobiomaterials for applications in ther- and other nanostructures, such as micelles, reverse apy, diagnosis, biosensing, bioanalysis and biocatalysis micelles and liposomes, which could be used as novel because nanobiomaterials for cell and organ chips [22– approaches for the large-scale production of program- 25], bioelectronic devices [26, 27] and biological separa- mable nanomaterials [18–20]. Te application of car- tion [28] have recently been reviewed in this journal. bohydrate polymers combined with nanotechnology in tissue engineering and medicine are also potential 2.1 Nanobiomaterials for therapy and diagnosis research felds for the development of novel biomate- Smart therapeutic and diagnostic or bioimaging NPs car- rials for biosensing, bioimaging, diagnostic and drug- rying cargo materials, such as drugs, DNAs, RNAs, pro- delivery systems [21]. teins, and imaging reagents, have been widely developed With either nanobiotechnology or bionanotech- [11, 13, 29–33]. To achieve intracellular NP and drug nology, biological molecules are indispensable build- delivery, many strategies for overcoming various bio- ing blocks for fabricating functional nanomaterials, logical barriers are needed, including the following: (i) nanodevices and nanosystems. However, from the preventing removal from the circulation by cells of the viewpoint of applying biological materials to nanotech- reticuloendothelial system; (ii) targeting specifc cells; (iii) nology, biological materials found in nature always have sufcient functions and properties. Recent advances in biomolecular engineering, such as genetic engineering, DNA and RNA engineering, protein engineering, site-specifc chemical and enzymatic conjugation technologies, self-assembly technology and massive high- throughput screening (HTS) methods, have enabled us to improve, stabilize, integrate and alter the functions and properties of biological materials. Tus, it is possi- ble to create engineered biological materials with functions and properties that are optimized for various uses in the felds of bioelectronics, biosensors, biocatalysis, molecular imaging, biological actuators, drug delivery systems, biomaterials for tissue engineering and regen- erative medicine. In this review, recent studies applying engineered biological materials to nanobio/bionanotechnology are discussed, and various biomolecular engineering technologies are highlighted. Fig. 1 A summary of nanobiomaterials and their applications Nagamune Nano Convergence (2017) 4:9 Page 3 of 56 internalization into cells; (iv) escaping from endosomes; growth factor, platelet-derived growth factor, and nuclear (v) trafcking to specifc organelles; and (vi) controlling factor kappa-light-chain-enhancer of activated B cells. the release of payloads (e.g., drugs, DNAs or RNAs). Specifc aptamers for targets can be selected from a large number of random sequences (libraries of 1015 random 2.1.1 Preventing removal from the circulation oligonucleotides) via the systematic evolution of ligands NPs made of hydrophobic synthetic polymers, metals by exponential enrichment

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