Bioinspired Design and Engineering of Functional Nanostructured

Chapter 7

Downloaded by UNIV OF FLORIDA on October 26, 2017 | http://pubs.acs.org Publication Date (Web): October 25, 2017 | doi: 10.1021/bk-2017-1253.ch007

Bioinspired Design and Engineering of Functional Nanostructured Materials for Biomedical Applications Xin Ting Zheng,1,4 Hesheng Victor Xu,1,2,4 and Yen Nee Tan1,3,* 1Institute

of Materials Research and Engineering (IMRE), Agency for Science, Technology and Research (A*STAR), 2 Fusionopolis Way, Singapore 138634 2Division of Chemical and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371 3Department of Chemistry, National University of Singapore, 3 Science Drive, Singapore 117543 *E-mail: [email protected] 4These authors contributed equally.

Nature has provided many ways to derive various functional materials with highly-ordered hierarchical structures and superb attributes from the sophisticated biological processes. Inspired by natural biomineralisation process, it has led to the emergence of four “bioinspired” strategies, i.e., bio-structure mimicking, bio-function anchoring, bio-templating and bio-assembling, to construct nanostructured materials with remarkable biomimetic properties. In this chapter, we will highlight the development of bioinspired approaches involving biomolecules and elucidate their roles in directing the bottom-up synthesis and programmable assembly of functional nanostructured materials. Their recent applications in diagnostics and therapeutic delivery will also be discussed. Finally, we will conclude this chapter with the challenges and future outlook of these bioinspired nanomaterials for the advanced biomedical applications such as theranostics.

© 2017 American Chemical Society Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


1. Introduction In today’s rapid advancing nanotechnological world, the synthesis of nanomaterials with superior qualities is highly imperative. Nonetheless, the preparation of nanoscale materials is very challenging. Fortunately, Nature has provided mankind with many hints and clues on how to develop complex functional materials. Biominerals, a type of organic-inorganic hybrid materials, possess a highly-ordered hierarchical structures with extraordinary physiochemical features including high flexibility, light-weight, exceptional mechanical strength and dynamic functions (1, 2). For instance, hydroxyapatite in bones and teeth of mammals, amorphous silica in diatoms and marine sponges, as well as as magnetite in chiton teeth (3–5), are the essential components in living organisms which support their important physiological functions. These biominerals are synthesized through an intelligent biological process called biomineralisation, whereby functional proteins facilitate the conversion of natural minerals into biominerals (6, 7). Although direct extraction to obtain these biominerals seems attractive, it involves tedious multistep processing such as identification, isolation and purification thus limiting its effectiveness (8, 9). Furthermore, these biominerals vary widely in their compositions and structures which might not be suitable for direct application. Instead, by studying the biological system and mimicking their forming mechanism, it would provide the guiding principles and further inspire us to design and develop nanomaterials with similar features. As such, this has led to the emergence of “bioinspired” approaches to fabricate nanomaterials with exceptional properties. Scheme 1 summarizes the general design strategies of bioinspired nanomaterials through bio-structure mimicking, bio-function anchoring, bio-templating and bio-assembling approaches. The “bio-structure mimicking” approach requires the profound understanding of the structure-function relationship of the natural materials as well as their physical and chemical principles, to enable the fabrication of bioinspired nanomaterials through replication of the nanoscale architecture of natural materials (10, 11). In this way, the synthetic nanostructured materials could mimic the functions of the nature made materials. Representative examples of bio-structure mimicking include the optical property of butterfly wing, adhesiveness of gecko foot and self-cleansing features of lotus leaves (12, 13). “Bio-function achoring” is another approach to render the nanostructured materials with desirable biological functions by chemically conjugating a specific biomolecule onto the as-synthesized nanomaterials. For example, specific proteins or carbohydrates could be anchored onto the nanomaterials to provide them with the unique bio-recognition and/or enzymatic ability that are inherited from the anchored biomolecular shell, and at the same time enhance the solubility and biocompatibility of the bio-nanocomposites (23, 24). “Bio-templating” is a synthetic approach of using biomolecule as a template to facilitate or direct the gowth of nanomaterials into various sizes and shapes (25–27). In a typical bio-templated synthesis of metal nanoparticles (NPs), biomolecules can be designed to act as a stabilizer and/or reducing agent to mediate the synthesis. It could also serve as a sacrificial template (or precursor) 124 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


to form the carbon-based nanomaterials as part of the hydrothermal synthesis process (28). Such approach is ideal as it does not require toxic reagents and harsh conditions, thus promoting a greener and more environmental friendly route for the NPs synthesis. Furthermore, the resulting biotemplated nanomaterials usually exhibit superb characteristics such as excellent biocompatibility, water solubility, rich chemical functional groups and tunable physiochemical properties (27, 29, 30). “Bio-assembling” is a self-assembly process of biomolecules, which has been recently explored to form different synthetic functional nanostructures. The underlying principle of this method is the self-assembling of biomolecules into stable and well-ordered structures through manipulating of their exceptional molecular recognition capabilities (31, 32). In particular, by manipulating the cognate Watson-Crick base pairing, single-stranded DNA (ssDNA) has been assembled into supramolecular structures such as two-dimensional (2D) DNA tiles (33, 34) and three-dimensional (3D) DNA origami (35, 36). Applying a similar principle, peptide sequences could be carefully designed to include both the hydrophilic and hydrophobic amino acid residues to form a peptide amphiphile (37). Through non-covalent interactions such as hydrogen bonding, ionic interaction, aromatic π – π stacking, hydrophobic and van der Waal’s forces, these peptide amphiphile would self-assemble into diverse 3D structures from nanofibrous network to hydrogel (38, 39). These bio-assembled nanomaterials represent an excellent platform for responsive loading and release of therapeutic agents (40).

Scheme 1. Bioinspired approaches to form functional nanostructured materials via bio-structure mimicking, bio-function anchoring, bio-templating and bio-assembling. Reproduced with permission from (14), Copyright 2013 Nature Publishing Group; Reproduced with permissions from (15–18), Copyright John Wiley and Sons; Reproduced with permissions from (19–21), Copyright 2011 American Chemical Society; Reproduced with permissions from (22), Copyright 2012 Elsevier. 125 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


In this book chapter, we will focus on the bioinspired materials design of using bio-templating synthesis and bio-assembling approaches to construct a variety of functional nanomaterials suitable for biomedical applications. By incorporating biomolecules, these bioinspired approaches promote not only a greener synthesis but also shortened the route of fabrication. Furthermore, they inherit the intrinsic characteristics possessed by biomolecules such as excellent biocompatibility, rich surface functional groups, good aqueous solubility and negligible toxicity that make them useful for biomedical applications. In addition, the composition and sequence of the biomolecules can be designed to fine-tune the morphology of inorganic nanostructures, and enable the programmable assembly of different higher-ordered biomolecular nanostructures with smart properties such as, dynamic control and stimuli responsiveness, for specific technological applications.

2. Bio-Templating Synthesis of Nanomaterials Bio-templating strategy, as the name suggests, uses biomolecules as templates to facilitate or direct the synthesis of nanomaterials. In the synthetic process, the biomolecules can either serve as preserved templates to be integrated into the final nanohybrids or will be sacrificed at the end of synthesis leaving the pure inorganic nanomaterial product with well-defined size, shape, and structure. Without the need to introduce toxic reagents and harsh condition, this approach represents a green, energy-efficient and eco-friendly way for nanomaterial synthesis (41, 42). In this section, the unique functionial properties of different biomolecules (e.g. nucleic acids, proteins and peptides) and their abilities to serve as a designable template to enable the synthesis of nanomaterials will be discussed. 2.1. Design of Preserved Bio-Template for Metallic Nanostructures Synthesis 2.1.1. Nucleic Acids as Bio-Templates Nucleic acids such as DNAs are natural biopolymers formed by long chain of nucleotides consisting of nucleobases such as Cytosine (C), Guanine (G), Adenine (A) and Thymine (T). The nucleobases are able to interact with their corresponding pair via Watson-Crick base pairing. Upon annealing with the complementary strand, the two ssDNAs would hybridise into a double helix structure with the negatively charged phosphate groups forming the backbone to minimise repulsion. As the phosphate backbones are highly negatively charged, they are able to bind cationic species such as metal ions via electrostatic interactions (43). Such interactions are able to stabilise the unstable intermediate cationic complexes. Likewise, the nucleobases such as C, G, A and T that contains the electron-rich nitrogenous group could potentially bind to and stabilise the cations and their intermediate complexes. Furthermore, they could also reduce electron-poor complexes through electron transfer mechanism (44). In a typical synthesis of metal NPs, metal precursors (e.g. Ag+) are first reduced to form nuclei and then grow into different nanostructures which are 126 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


stabilized by capping agents. Since the formation of metal NPs is driven by the capping and reducing capabilities of the ligands, these corresponding properties of nucleic acids are critical in the bio-template design for NP synthesis. For instance, the negatively charged phosphate groups are able to bind to and stabilise the positively charged metal ions such as Ag+ and Au+ via electrostatic interactions (45, 46). External stimuli such as UV light could be irradiated to induce a reducing environment allowing metal NP nucleation (47). Since double-stranded DNAs (dsDNAs) are rigid molecules with linear structures, the metal nuclei could subsequently grow along the dsDNA nanostructure and gradually forming a nanowire (48). It is worth noting that the stabilisation of Ag/Au intermediate complexes by the phosphate backbone is sufficient to prevent aggregation of the resultant NPs. Besides dsDNA, ssDNA has also demonstrated high efficiency in seed-mediated growth of metal NPs. Unlike dsDNA, ssDNA has exposed nucleobases which are strong electron donors. Thus, they are not only capable of binding to the electron-poor metal ions, but also able to reduce the metal ions for nucleation and growth. For example, it is found that the nucleobases in ssDNA could bind to Ag+ with different affinities (i.e. C > G > A > T) and different Ag nanostructures such as nanocubes, nano-octahedron and nanoflowers have been obtained by varying the sequences (49–51). As the molecular structures of DNA templates are preserved throughout the synthesis, some of these DNA-templated NPs retain the molecular recognition functions of the DNAs, endowing them with intrinsic sensing capabilities for diagnostic applications. This is especially true with plasmonic NPs such as AuNPs or AgNPs as they possess unique interparticle-distance dependent localized surface Plasmon resonance properties (53, 54). For instance, their high extinction coefficient are sensitive enough to induce noticeable colour change and detection by naked eyes (55, 56). With the target-specific binding of DNA preserved, these DNA-AuNPs or DNA-AgNPs could form aggregation or dispersion depending on their biomolecular interactions with target analytes, providing a basis for colorimetric sensing (57, 58). Particularly, Liu et al. have demonstrated the use of DNAzyme-AuNP as a highly sensitive and selective colorimetric assay for Pb(II) detection (59). Upon hybridisation, the AuNP aggregates, resulting in a blue-coloured solution. In the presence of Pb2+, hydrolytic cleavage occurs, preventing the aggregation, producing a red-coloured solution of well-dispersed AuNPs. In another report, Lin et al. have described the use of a DNA-AgNP as a platform for a simple fluorescence turn-on detection of dopamine (DA) (Figure 1) (52). Since DAs are able to form strong Ag-catechol bonds, DA addition released AgNPs from the DNA and a fluorescent signal was produced in the presence of intercalating DNA dyes. Using a similar strategy, detection of thiol-containing biomolecules were also reported (60, 61). More recently, nucleic acids were also exploited as templates to mediate the synthesis of metal nanoclusters (NCs), a new class of luminescent nanomaterial. These metal NCs exhibit ultrasmall size of < 2 nm, which lead to strong quantum confinement effect, thus bestowing them with bright photoluminescence (63). In particular, AgNCs are commonly synthesized using nucleic acids due to the strong binding affinity between Ag+ and nucleobase C, which could stabilise the intermediate complex and serve as a nucleation site for AgNCs (64, 65). 127 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Compared to typical NP synthesis, these ultra-small fluorescent NCs require a more meticulous and stringent preparation. For instance, it was found that slight variation in the overall DNA length and/or sequences would alter the fluorescence properties of the AgNCs such as the emission wavelength and the photostability (66–68). As such, a careful design of DNA sequences is critical. Notably, Guo et al. reported a C6-loop with C-C mismatch to first entrap the Ag+ and then gradually reducing them to form AgNCs (69). By manipulation of the base pair mismatches and a basic sites to produce Ag binding sites, other DNA supramolecular structures such as the i-motif (70), DNA duplex (71) and the G-quadruplex (72) have also been explored to synthesize bio-templated AgNCs. Similar to DNA-templated metal NPs, these DNA-AgNCs could also function as an excellent sensing platform. Instead of colorimetric assay, they could be developed as fluorometric assays due to their intrinsic fluorescence characteristics. For example, Yeh et al. have observed that the fluorescence of DNA-AgNCs could be enhanced when comes in close proximity with G-rich DNA sequences (73). Based on this observation, they have further developed a NanoCluster Beacon (NCB) to detect an influenza sequence. Applying a similar strategy, Yin et al. prepared a system of DNA-AgNCs for cancer cell detection (Figure 2) (62). The system consists of two tailored DNA probes, one containing sequence for AgNCs template synthesis while the other comprises of G-rich DNA sequence at 5′-end and a cancer targeting aptamer sequence at 3′-end. Upon detecting CCRF-CEM cancer cell, the recognition probe would undergo conformation change, giving out a fluorescent signal.

Figure 1. (A) Schematic representation of using DNA-templated AgNPs and intercalating dye Genefinder (GF) for dopamine (DA) detection. (B) Fluorescence emission spectra of GF/dsDNA–silver nanohybrids in the presence of increasing DA concentrations (0-0.5μM). (C) Fluorescence intensity at 525nm as a function of the DA concentration (0-0.5μM). Reproduced with permission from (52), Copyright 2011 John Wiley and Sons Ltd. 128 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 2. (A) Schematic Illustration of an aptamer based AgNC assay for the label-free and fluorescent turn-on detection of cancer cell. The fluorescence responses of aptamer TD05 involved in recognition probe to assay target Ramos cancer cells by (B) flow cytometry and (C) confocal microscopy images. Reproduced with permission from (62), Copyright 2013 American Chemical Society.

Further on, photoinduced electron transfer of DNA-AgNCs was also explored. Wang’s group prepared a functional DNA-AgNCs that is capable of detecting hemin biomolecule using a parallel G-quadruplex and a hemin specific sensing sequence (74). Upon detection of complementary sequence, the G-quadruplex would be released and subsequently captures the hemin biomolecule, forming a stable G-quadruplex/hemin complex. This formation promotes electron transfer from DNA-AgNCs to the hemin complex, thus reducing the fluorescent intensity of the former. Other DNA templated NCs such as DNA-CuNCs have also shown potential to be used as a biosensor. For instance, Zhou et al. developed a label-free aptamer sensor for adenosine triphosphate (ATP) by controlling the 129 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


formation of DNA-CuNCs (19). Since CuNCs would only form in the presence of dsDNA but not ssDNA, the existence of ATP would bind strongly to one of the strands, inhibiting the growth of CuNCs. This simple detection for ATP has a preferable linear range (0.05-500 μM) and a high sensitivity with detection limit of 28 nM. Likewise, Wang’s group exploited this strategy to test for single nucleotide polymorphism (75). Compared to the perfectly matched DNA, it was found that the mismatch base pair site would provide an appropriate environment for CuNCs, altering their fluorescent intensity. The differences in fluorescence intensity were highly dependent on the mismatch sequence which allows the detection of more than one mismatches in a specific DNA sequence. Besides sensing of biomolecules, detections of other ions such as Pb2+ and S- have also been demonstrated (64, 76, 77). In general, nucleic acids are good stabilising and reducing agent which serves as an excellent designable bio-template to direct the synthesis of metal NPs. Such methodology promotes the green synthesis of metal NPs and renders inherent biocompatibility to the nanohybrid. Furthermore, as the bio-templates are preserved after the synthesis, it endows them with the unique biorecognition capability for direct biosensing and diagnostic applications without post functionalization.

2.1.2. Proteins as Bio-Templates

Proteins are a class of biomacromolecules with complex three-dimensional (3D) architecture. The protein structures which constitute of amino acids as basic building blocks, have diverse functional groups such as -NH2, -CO2H, -OH, -SH in their side chains for chemical synthesis and modications. Some of the functional groups of amino acids residues such as tyrosine (Tyr) (78), aspartic acids (Asp) (79, 80) trytophan (Trp) (81), lysine (Lys) (82) and cysteine (Cys) (83, 84) have been shown to be good reducing agents and/or stabilising agents, which could provide specific binding and nucleation sites for metal ions. For example, Tyr residues in the BSA protein template are found to be responsible for the reduction process of Au+, leading to the formation of spherical AuNPs (85, 86). Conversely, Casein protein which forms micelle structure in aqueous environment, uses its Asp residues to bind to and reduce Au+, producing anisotropic Au nanoplates (87). As mentioned previously, the formation of NCs involves a more rigorous requirement in the bio-template design. In particular, the bulky proteins could introduce steric hindrance, providing sufficient stabilizing effect to promote the formation of NCs. For instance, bulky proteins such as transferrin (88), lactoferrin (89), lysozyme type VI (90), horseradish peroxidase (91), trypsin (92) and insulin (93) which contain Cys residues could provide sufficient steric hindrance as well as forming Au+-thiolate intermediates to stabilise the growth of protein-templated AuNCs effectively (94, 95). 130 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Similar to DNA-templated metallic nanostructures, the protein templates also retain their initial bio-recognition functions after the bio-templating synthesis, enabling them to act as diagnostic sensors. For instance, lysozyme-AuNCs were found to be able to retain their bioactivity, allowing them to label bacteria such as E.coli and inhibit their growth (96, 97). In another example, Wang et al. prepared a transferrin-AuNCs coupled with sheets of graphene oxide (GO) for cancer cells diagnosis and imaging (98). The nanocomposite has a “turn-on” fluorescent feature which could display near infrared (NIR) fluorescence upon identification of the transferrin receptor on the surface of the cancerous cell both in vitro and in vivo. In addition, Ranjita et al. utilised protein seeding of AuNPs via glycosylated haemoglobin to study the mechanism of glycosylation and sense the glycosylated end products by solution color changes due to the changes in AuNPs size (99). The size increase of the AuNPs could be observed through transmission electron microscopy (TEM) while the structural alterations of the proteins were investigated using infrared spectroscopy and circular dichroism. Besides the bio-recognition ability, BSA-AgNCs synthesized by Yu et al. displayed strong singlet oxygen generation capacity with a quantum yield of ~1.26, and exhibited excellent cellular uptake and biocompatibility which demonstrated a high anticancer efficacy via photodynamic therapy (100). Using similar strategies of reduction and stabilisation, protein cages such as apoferritin, viral capsid, heat shock protein and lumazine synthase have also been demonstrated as efficient templates for the preparation of nanomaterials (101–103). In particular, apoferritin has been used to synthesize magnetic NPs such as Fe (104, 105), while other metal NPs like Ni (106), Cr (107), Cu (108), Au (34), Ag (109), and semiconductor NPs such as CdS (110) and CdSe (111) have also been reported. Ferritin (Fn) has a nearly spherical structure with a negatively charged channels containing amino acids such as Asp and Glu, could bind to and transport positively charged metal ions to its hollow cavity (112, 113). The encapsulated metal ions could be reduced using UV light or heating and the resulting NPs would be stabilised by the neighbouring carboxylate groups in the cavity (114, 115). The as-synthesized Fn-NP could be used for diagnostic or therapeutic applications due to the distinctive properties of the cage-enclosed metal NPs. For example, Li et al. prepared a Fn-Fe3O4 nanostructures for tumor sensing and imaging (116). The surface of Fn was conjugated with cancer targeting RGD peptide and a green fluorescent protein, combined with the magnetic resonance imaging capability of Fe3O4 NPs, the nanoproduct could specifically target and track cellular uptake by tumor cells. On the other hand, Wang et al. prepared a CuS-Fn nanocage which achieved superior cancer therapeutic efficiency using photothermal therapy (Figure 3) (117). Moreover, the nanocages are also excellent positron emission tomography (PET) and photoacoustic imaging (PAI) agent which provide real-time monitoring and guidance of the nanocage in vivo. The theranostic potential of Fn-NP has also been illustrated recently by Ceci’s group (118). By decorating the surface of Fn with melanoma targeting peptide and poly(ethylene) glycol (PEG), and doping the Fe3O4 core with Co2+, the resulting magnetoferritin exhibit excellent targeting properties, outstanding in vivo stability, enhanced magnetic anisotropy and hyperthermic effect toward melanoma cancer cells. 131 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 3. (A) The preparation procedure of CuS−Fn NCs; TEM images of (B) iron free Fn and (C) CuS−Fn NCs stained with 1% uranyl acetate; (D)Temperature recording of U87 MG tumour mice upon 5 min laser exposure of different powers; (E) The variation of temperature in tumour area upon laser irradiation; (F) Images of U87MG tumour mice at various days after treatment. Reproduced with permission from (117), Copyright 2016 American Chemical Society.

2.1.3. Peptides as Bio-Templates In contrary to proteins, peptides compose of shorter chain of amino acids, which provide a more versatile platform for bio-templating synthesis due to the absence of complex secondary and tertiary structures. Through careful selection of amino acid residues, the peptide could be programmatically designed into an efficient template to direct the synthesis of metal NPs. For instance, Tan et al. conducted a systematic study to uncover the design rules for peptide synthesis of AuNPs (Figure 4) (119). They demonstrated that through combining amino acids such as Tyr and Trp with the shape-directing sequences respectively, the resulting 132 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


peptides (i.e. SEKLWWGASL and SEKLYYGASL) were able to synthesized Au nanoplates from AuCl4- precursors in one pot solution. Moreover, other peptides such as Ac-TLHVSSY-CONH2 and SSFPQPN were also designed to facilitate the formation of platinum nanocrystals (120, 121).

Figure 4. (A) Schematic illustration for the peptide mediated synthesis of AuNPs in aqueous solution. The peptides and chloroaurate ions were first interacted to form peptide-AuCl4 complexes, facilitating the reduction of Au ions to Au(0) in forming nuclei. It is followed by the growth of nuclei into crystalline particles induced by the addition of more Au atoms from the solutions or by fusion with other nuclei. (B) The molecular interactions between peptide and Au ion, as well as peptide and gold atoms which determined the reactivity of functional peptide template for metal NPs synthesis can be designed by the selection of amino acids and their sequences. TEM images of AuNPs synthesized from using multifunctional peptides (C) SEKLWWGASL and (D) SEKLYYGASL. Reproduced with permission from (119), Copyright 2010 American Chemical Society. Other than synthetic peptides, naturally occurring peptides such as glutathione (GSH) were utilised in the synthesis of ultrasmall AuNCs. Being a short chain peptide, the GSH peptides could facilitate the reduction of Au+ to Au0 while stabilising the Au+ intermediate by binding through carboxylate and thiol functional groups (122). The as-synthesized protein- and peptide-based metallic nanostructures could also be used as promising biosensing probes owing to the conserved biorecogntion functions of the template. This includes the detection of enzymes (123, 124), small molecules (125, 126) and metal ions (127–130). Remarkably, peptide-NCs are able to produce near-infrared emission wavelength upon excitation, allowing them to activate any photosensitizer to yield reactive oxygen species (ROS) such as singlet oxygen for potential photodynamic therapy (PDT). For instance, Zhang et al. fabricated a GSH-AuNCs functionalized with folic acids and PEG on the surface, to enable the entrapment of photosensitizer 133 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


chlorin e6 (131). The in vitro and in vivo studies show the enhanced cellular uptake and satisfactory PDT effectiveness toward cancerous MGC-803 cells. More recently, Vankayala et al. reported a TAT (cell penetrating peptide)-AuNCs that could perform simultaneous in vitro and in vivo fluorescence imaging, gene delivery, and NIR activated photodynamic therapy for effective anticancer therapy (132). The positively charged nanoprobe could load the negatively charged DNAs via electrostatic interactions and transport them into the nucleus for successive transfection. Furthermore, the nanoprobe could also generate ROS to induce cell apoptosis without the use of any organic photosensitizer. Proteins/peptides offer an excellent platform for the bioinspired design and engineering of metallic nanostructures of different size, shape and properties. Specifically the biomolecular shell of the metallic nanostructures could endow them with good biocompatibility and a diverse functional group such as NH2, COOH and SH for further conjugation of therapeutic and/or diagnostics agents for biomedical applications.

2.2. Design of Sacrificial Bio-Templates for Carbon Nanomaterials Synthesis Besides functioning as a bio-template that can be preserved throughout the bioinspired synthesis process, biomolecules such as nucleic acids, proteins, peptides, amino acids and carbohydrates could also be used as sacrificial templates in the synthesis of carbon nanomaterials. Particularly, “bio-dots”, the biomolecule-derived fluorescent nanodot, represent a new class of fluorescent nanomaterial synthesized using biomolecules as the sacrificial templates (133–135). Abundant with elements such as oxygen, nitrogen, phosphorous and sulphur, biomolecules are good doping agents in the preparation of the bio-dots. By introducing heteroatom doping, it provides various trapping sites of different series of energy levels in bio-dots (136, 137). This enables electronic transitions such as π→π* and n→π* transitions, allowing emission of photons with varying excitation energy. Therefore, the use of biomolecules could endow these bio-dots with interesting optical properties that are desirable for biomedical applications (138). In one example, Du et al. synthesized nitrogen doped nanodots using glucose and serine as precursor (139). The surface of the nanodots were passivated with functional groups such as C-O, C=O and O=C-OH which provided surface defects with different energy levels, granting the nanodots with excitation-dependent properties. Upon incubation with A549 cells, the nanodots could be readily uptaken by the cells, displaying multiple fluorescence emission wavelengths (i.e. blue, green and red). Correspondingly, Sun’s group prepared Asp derived bio-dots to diagnose brain cancer (Figure 5) (140). The Asp-dots (CD-Asp) not only exhibit tunable full-colour emission with a quantum yield of 7.5%, but also possess intrinsic selectivity and targeting affinity towards cancerous C6 glioma cells. Both in vitro and in vivo studies showed high biodistribution of Asp-dots located to the brain tumor indicating their potential application as an excellent bio-imaging and diagnostic agent. 134 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 5. (A) TEM, (B) High-resolution TEM images of CD-Asp; (C) In vivo imaging of glioma-bearing mice at different time points after injection with CD-Asp, CD-G, and CD-A. Reproduced with permission from (140), Copyright 2015 American Chemical Society. In addition to surface passivation, the biomolecules also supply the bio-dots with rich chemical functionalities for linking targeting moieties and/or drug molecules. For instance, Sharon and co-workers prepared a fluorescent dots from sorbital via microwave-assisted heating (141). The sorbital bio-dots were first attached onto BSA surface via electrostatic attractions and then further functionalized with cancer targeting ligand, folic acids and anticancer agent, doxorubicin (dox). The resulting complex could be applied as anticancer theranostics. On the other hand, Shen’s group utilised DNA from E.coli to 135 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


synthesize fluorescent bio-dots (142). The surface of DNA dots was grafted with functional groups such as C−OH, N−O, and N−P resulting in a negative zeta potential, enabling electrostatic dox loading. Due to the inherent fluorescence from DNA dots, the nanocomplex was able to induce cell apoptosis and at the same time allowed real-monitoring of the drug release process. On the whole, biomolecules could serve as an efficient precursor in the synthesis of carbon nanomaterials such as bio-dots. Although the overall secondary or tertiary structure of the biomolecule may be altered or completely destroyed in the process, their inherent properties such as aqueous solubility, rich chemical functional groups and excellent biocompatibility are still imparted to the bio-dots. This makes them potentially useful in various biomedical applications such as imaging, diagnostic and therapeutic delivery.

3. Bio-Directed Assembly of 3D Smart Nanostructures Molecular self-assembly mechanism underlies the organization of biological systems. Natural biopolymers such as nucleic acids and peptides can self-assemble into well-defined nanostructures in a programmable manner based on the information encoded into their primary structure - their sequences. In recent decades, the principle of molecular assembly is employed to achieve bottom-up synthesis of nanostructured materials, whereby material functionalities and properties depend on the “bio-directed assembly” of basic biomolecular building blocks. So far, a wide range of smart nanostructures has been formed based on the self-assembling capabilities of biopolymers. The nanostructures are either composed exclusively of biomolecules or consisting of inorganic NPs complex assembled by the biomolecular scaffold. In addition to the bio-assembly of static nanostructures, dynamic assembly of intelligent nanomaterials that is stimuli-responsive, error-free and reversible is also highly desirable to create molecular machines (143).

3.1. Nucleic Acid-Directed Assembly Nucleic acids not only carry the genetic information for heredity; but are also powerful nanotools for the bottom-up assembly of nanomaterials. Their minuscule size (diameter < 2 nm), short structural repeat of helix (~3.4-3.6 nm), inherent complementary base pairing property and the sequence programmability make them excellent linkers in constructing highly structured materials with precise spatial and dynamic control. Chemically modified DNAs are able to functionalize different nanomaterials such as AuNPs, quantum dots, and carbon nanotubes, leading to the formation of various hierarchical structures. In addition, specifically designed DNA motifs could self-assemble into one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D) nanostructures, which could in turn act as scaffolds to direct the assembly of inorganic NPs. Furthermore, a special group of functional nucleic acids, for instance, DNAzymes with enzymatic 136 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

activity and aptamers with recognition properties are ideal for constructing the stimuli-responsive and reversible assembly of nanostructured materials (144).


3.1.1. Design of Chemically Modified DNA Linkers To Create Geometrical Nanostructures Mirkin et al. pioneered the use of chemically modified DNA oligomers to connect nanoparticles into nanoassemblies (145). In this approach, two thiolated non-complementary DNA sequences were functionalized onto two sets of colloidal AuNPs via Au-S chemistry. When a dsDNA with “sticky ends” that are complementary to the two grafted sequences, the two sets of AuNPs will self-assemble into large aggregates (145). A sticky end is a few unpaired nucleotides extending from the end of a dsDNA, which offers both excellent control of intermolecular interactions and predictable geometry at the point of association, and they are the key to the formation of various DNA nanostructures via ligation. Similarly, Alivasato et al. demonstrated a more discrete organization of AuNPs into dimers or trimers by mixing short ssDNA modified AuNPs with a well-designed complementary ssDNA template (146). Through careful design of dsDNA sequence, various well-defined nanostructures with nonlinear geometries such as triangles, pyramids, cubes and polyhedral have been developed through the years (147–152). For example, discrete DNA pyramids with AuNPs at the tips have been created, and biomimetic chiral nanostructures have been demonstrated using four sets of AuNPs with different diameters (153). This strategy of using DNA scaffold to control the placement of NPs has opened up many opportunities to enhance the functionality of pure DNA nanostructures. In addition to the assembly of single type of NPs, Yan et al. prepared a collection of DNA-assembled heteroparticle chiral pyramids from multiple metal and/or semiconductor NPs with an 80% yield. They were able to correlate the optical properties of these systematically assembled heteroparticle pyramids to their chirality (154). Willner and co-workers then introduced a new paradigm to construct tether-modified DNA scaffolds to organize left- or right-handed plasmonic helices of AuNPs (155). Recently, researchers started to utilize 3D DNA nanostructures for various biomedical applications. For example, Leong and co-workers developed a theranostic DNA nanoscaffold by decorating them with fluorescent AuNCs through covalent functionalization and intercalating therapeutic Actinomycin D for simultaneous detection and killing of E. coli and S. aureus (156). The same group also reported a bioinspired DNA nanosensor comprising of a molecular beacon module to a DNA nanoshell for real-time detection of mRNA in living cells (157). A DNA tetrahedron loaded with the chemotherapy drug and photosensitizer linked to a circulating tumor cells (CTC) targeting aptamer has been used to sense and treat CTCs effectively. In general, these DNA nanostructures show many advantages including enhanced cellular uptake, increased drug loading and synergistic therapeutic effect by combined loading of several therapeutic agents (158). 137 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


3.1.2. Design of DNA Tiles for Bottom-Up Assembly of Complex Nanostructures Seeman et al. are the first to design and synthesize DNA tiles which include various DNA motifs such as four-way branched junctions (159, 160), and double-cross-overs (DX) (161) to construct complex DNA nanostructures such as 2D arrays (162), cubes (147), and octahedrons (150, 159, 163). As shown in Figure 6A, the synthetic branched DNA junctions mainly consist of three or four arms of dsDNAs. Half of each ssDNA contributes to one arm, while the other half is paired with a neighbouring arms. Thus, all the arms of the branched junction are connected to each other at a central point (164). For example, a truncated octahedron (molecular weight ~ 790 kDa) was assembled from well-designed cyclic DNAs on a solid support. Six cyclic ssDNA molecules were used to form the six squares and the extra arms. The eight hexagons were constructed from another eight cyclic strands (148). In a similar way, the combined application of branched DNA junctions with sticky-end ligation has led to the successful construction of multiply connected objects, networks and devices. However, these branched DNA junctions are usually too flexible to form regular higher order structures.

Figure 6. (A) Self-assembly of branched DNA junctions into a 2D crystal. Reproduced with permission from (150), Copyright 2003 Springer Nature. (B) Typical DNA motifs including double-crossover (DX), triple crossover (TX) and paranemic crossover (PX) tiles. Reproduced with permission from (168), Copyright 2003 Elsevier. (C) Three-dimensional(3D) structure of DNA octrahedron. Three views of the 3D map generated from reconstruction of the DNA octahedron (Top, right). Raw images of individual DNA octrahedron and corresponding projections of the 3D map (Bottom, right). Reproduced with permission from (151), Copyright 2004 Springer Nature. 138 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


To tackle this rigidity problem, a stiffer motif called DNA double-crossover (DX) tile, which contains two dsDNAs connected to each other at two crossover points (Figure 6B), are used for constructing 2D arrays (150). Besides individual nanostructures, the assembly of periodic nanostructures have also been demonstrated by designing the sticky ends on one side of the DNA tile to be complementary to the other side (149). In addition, triple crossover (TX) tiles consisting of three in-plane DNA helices connected through crossover points and paranemic crossover (PX) tiles comprising of two parallel double helices fused at every possible cohesion point by reciprocal exchange have also been developed as basic building motifs (Figure 6B) (164). The replication/cloning of large 3D geometric DNA objects are very challenging. Shih and co-workers are the first to demonstrate a well-designed 3D DNA structure assembled from a readily amplifiable 1669-nucleotide ssDNA molecule. As illustrated in Figure 6C, this ssDNA was folded into an octahedron spontaneously with the addition of five 40-mer synthetic DNA (151). This DNA octahedron consists of five DX structures and seven PX (165) structures joined at six four-way junctions. Different from previous multistep assembly approaches, Erben et al. introduced a novel design principle which allows rapid assembly of DNA tetrahedra from multiple strands in one step with high yield (166). The same design principle has been extended to create a trigonal biypramid from six DNA strands with close to 40% yield (152). Instead of designing multiple DNA motifs to form different DNA structures, Mao’s group are the first to propose a three-point star tiles which could be assembled into various larger 3D hierarchical structures using the same basic building blocks. Tetrahedra, dodecanhedra or buckyballs have been also assembled in one pot from four, twenty or sixty tiles, respectively (167).

3.1.3. Design of DNA Origami as Addressable 2D/3D Scaffolds In 2006, Rothemund proposed “DNA origami”, a modern technology to construct larger and more complicated DNA nanostructures (163). DNA origami are arbitrarily shaped structures formed from the folding of a long ssDNA scaffold fixed by several smaller staple strands to create multiple double-stranded sites and consequently achieve a rigid 2D structure (170). Using this approach, several 2D shapes including rectangle, stars, and smiley faces have been created. Later on, the Shih’s group reported a breakthrough in DNA origami by building various 3D structures with excellent control. The key to the successful constructions of such 3D architecture is the optimized design of the staple strands to allow formation of Holliday junctions at specific locations. They further developed a computer program to expedite the design of complex DNA origami (170). Another notable contribution by Shih’s group is the creation of curved origami with delicate control of both the twist direction and the bending angle (171). DNA origami provides an excellent framework to create nanohybrid structures. Schreiber et al. have applied DNA origami as scaffolds to achieve hierarchical assembly of metal NPs, quantum dots as well as organic dyes in a planet-satellite construction with excellent control over both distance and stoichiometry (Figure 7) (169). 139 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


Figure 7. (A) A ssDNA scaffold (~8 kb) is annealed with ~200 synthetic oligonucleotide staples (~40-mer) to create various DNA origami structures of defined shape and size. (B) Satellite nanoparticles functionalized with multiple thiolated DNA strands are hybridized to the DNA origami structures. (C) The nanoparticle bearing DNA origami structures are hybridized to planet nanoparticle. (D) Au nano origami cluster with 60 nm AuNP planet and 10 nm AuNP satellites. (E) Ag–Au nano origami cluster with 80 nm AuNP planet and 20 nm AgNP satellites. Reproduced with permission from (169), Copyright 2014 Springer Nature.

3.1.4. Design of Functional Nucleic Acids for Dynamic 3D Assembly Certain nucleic acid sequences such as i-motifs undergo conformational transitions upon environmental stimulation thus making them especially suitable for creating smart molecular devices/machines. In addition, functional nucleic acids such as DNAzymes, aptamers are suitable for dynamic 3D assembly of novel structures from various NPs (AuNPs, quantum dots, carbon nanotubes, and iron oxide NPs). To achieve stimuli-responsive assembly, for example, assembly and disassembly of AuNP networks can be controlled by DNAzymes or aptamers that undergo dehybridization or conformation change in response to metal ions (172), small organic molecules (173) or even proteins. For instance, Lu et al. applied both DNAzymes with high metal selectivity and metallic NPs with strong distance-dependent optical properties in a ‘tail-to-tail’ configuration for fast colorimetric sensing of Pb2+ ions (172). Smart design of multiple aptamer or aptazyme sequences enable the selective responses to multiple stimuli just like an AND/OR logic gate (174). For assembly with error correction, proofreading and error removal can be achieved by combining both a cleavage and a ligation 140 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.

DNAzyme in an enzyme cascade. Furthermore, Lu and co-workers have taken advantages of the different binding affinities between biotin and desthiobiotin toward streptavidin to construct a controlled reversible assembly of strepavidins to convey an encrypted message on DNA origami (175). DNA based smart assembly has led to the development of a variety of smart molecular machines such as molecular switches, molecular motors, molecular walkers, switchable materials/devices. Furthermore, the advancement in this field has recently revolutionized DNA computation and molecular programming.


3.2. Peptide-Directed Assembly Similar to nucleic acid, peptide which consists of amino acids, is another popular biomolecular building block for assembly of various supramolecular structures. Peptides are attractive because of its good biocompatibility, biodegradability, low immunogenicity, structural programmability, versatile functionality as well as cost-effectiveness of large scale production via standard solid-phase synthesis. It is worthy to note that an enormous opportunity arises from the combinatorial complexity of the peptide sequences since they comprise 20 naturally occurring amino acids with different properties as building blocks and exhibit a wide range of chemical functionalities. To illustrate, the diverse properties of amino acids include charged (D, E, H, R, and K), polar (S, T, Q and N), nonpolar (A, V, L, I and M), aromatic (F, Y and W) and other special residues (P, C and G). The properties of individual amino acid residue can contribute differently toward the overall properties of resulting peptides, which subsequently determine the final supramolecular structures (176). The assembly of ordered peptide nanostructures is a spontaneous thermodynamic and kinetic driven process, controlled by the synergy of various intermolecular non-covalent interactions including hydrogen bonding, π-π stacking, electrostatic, hydrophobic and van der Waals interactions (177). As a result, peptide self-assembly has created various architectures over a large length scale ranging from nanoscale to macroscale with various 2D conformations such as α-helix and β-sheet. Frederix et al. recently demonstrated a computational tool to screen the self-assembly possibility of 8,000 tripeptides in aquesous medium and develop important design rules for self-assembling sequences (178). Three main ways to achieve peptide self-assembly by using 1) short diphenylalanine based aromatic peptides, 2) peptide amphiphiles and 3) more complex long polypeptides (> 20 amino acids) are discussed in details in this section.

3.2.1. Diphenylalanine-Based Aromatic Peptides Short peptide motifs containing aromatic groups can self-assemble in aqueous medium. Reches and Gazit observed that the self-assembly of diphenylalanine (FF), a fragment of Alzheimer’s β-amyloid protein into discrete nanotubes (179). 141 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


It is know that amyloid fibrils are highly organized protein aggregates that play a physiological role in microorganisms and melanin-producing mammalian cells. They can readily form nanofibers and nanotubes. Similar to the naturally occurring amyloids, the ordered organization of the unique peptide nanostructures comes from the cooperated effects of hydrogen bonding and π-π stacking in the FF dipeptides. A pathway for FF dipeptides to form nanotubes has been proposed whereby FF dipeptides first stack up to form a 2D layer and subsequently this 2D layer closes up to form a tubular structure (Figure 8A). This peptide nanotube can further act as a bio-template to form silver wires with a micrometer persistence length. Other aromatic dipeptides such as WY, WF and WW were unable to form any nanotubular structure. For FW peptides, nanotubes and amorphous aggregates were formed at the same time. Later on, FF dipeptides have been assembled into a variety of complex architectures such as vesicles, hexagonal microtubes, ordered chains, nanowires (180) and nanofibers (177, 181). These peptide nanostructures could be used for bioimaging, biosensing, drug delivery, 3D cell culture and nanofabrication. The short FF-based peptides are very popular building blocks due to simple structure, versatile functionalities and cost-effectiveness. To improve their functionality, they could integrate with inorganic components to direct the synthesis of metal nanowires, nanoribbons and polymers.

3.2.2. Peptides Amphiphiles

In general, peptide amphiphiles consist of a short hydrophobic chain linked with a short hydrophilic peptide sequence. They possess both the structural feature of an amphiphilic surfactant and the biological activity of a peptide. In detail, a peptide amphiphile molecule consists of four domains including an aliphatic tail (I), an β-sheet forming sequence (II), several charged amino acids to offer solubility and induce crosslinking (III) and a signalling peptide for biological response (IV) (182). Modifications of the typical peptide amphiphiles have been developed to suit specific applications. For example, a fibronectin-mimetic peptide amphiphile sequence was design to compose of both RGD and PHSRN binding domain, which renders superior cell adhesion properties (Figure 8B) (183). In most cases, their linear hydrophilic head and hydrophobic tail structure determines whether spherical micelles, cylindrical micelles or lamellar structures are formed under physiological conditions, which leads to interesting applications in tissue engineering, regenerative medicine and drug delivery (184). An alternative approach is to rely on the synthetic aromatic groups such as fluorene, naphthalene, azobezene, pyrene or phenyl groups to confer the amphiphilicity required to initiate and drive self-assembly. This special class of peptide amphiphiles is commonly named as aromatic peptide amphiphiles. A typical aromatic peptide amphiphile is a short peptide sequence capped with a synthetic aromatic moiety at the N-terminus (176). Different from their aliphatic 142 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


counterparts, the assembly of these aromatic peptide amphiphiles are controlled by both the stacking interactions and the β-sheet forming hydrogen bondings. Thus, the assembly process is also affected by the planarity of the aromatic cap and the geometric restrictions of their stacking arrangement. The aromatic peptide amphiphiles have led to the successful formation of nanoscale spheres, worms, sheets, tapes and fibers/tubes (176).

Figure 8. (A) A proposed formation pathway of diphenylalanine (FF)-based nanotubes. Reprinted with permission from (181), Copyright 2010 Royal Society of Chemistry. (B) Self-Assembly of fibronectin mimetic peptide amphiphile nanofibers. TEM image of the assembled nanofiber is displayed on the right. Reprinted with permission from (183), Copyright 2010 American Chemical Society. (C) Design of the self-assembling polypeptide tetrahedron. Reprinted with permission from (185), Copyright 2013 Springer-Nature.

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3.2.3. Polypeptides Synthetic polypeptides are polymers composed of many amino acids (>20 residues) and they typically assemble into random coil, α-helix and β-sheet. The conformation is correlated with the polypeptide solubility and rigidity in solutions. Higher solubility favours the random coil structure (177). These polypeptides can be developed into a diverse range of nanostructures including nanofibrils, lamellae with stimuli-responsive properties. For instance, the hydrogen bondings and hydrophobic interactions between polypeptides are highly temperature dependent. Thus, a small change in temperature can easily alter the secondary structures of polypeptides. Temperature treatment has been demonstrated to change the secondary structures of polypeptides from α-helices to β-sheets, consequently leading to an overall structural transition from micelles to nanoribbons (186). In one example, Padilla et al. presented a modular approach to design symmetrical peptide nanostructures. This general strategy enables the successful construction of tetrahedral cages from 12 subunits, including 6 pairs of coiled-coil forming peptides, 2 antiparallel dimers and 4 parallel dimers (187, 188). In another example, a strategy was develop to form self-assembling polypeptide polyhedron from orthogonal dimerizing segments (Figure 8C). Jerala and co-workers successfully constructed a tetrahedron from a single polypeptide chain comprising of 12 coiled coil-forming segments separated by flexible peptide hinges (185). This polypeptide design principle provides a foundation for self-assembly construction of novel polypeptide nanostructures. In comparison to DNA nanostructures that are based on complementary base pairing, the peptide-directed assembly of nanostructures is far more sophisticated due to the complexity in long-range cooperative interactions between different amino acids, which is not easily predictable from the primary structure. DNAs as nanostructure building blocks have demonstrated great success, peptides may provide larger conformational variability and consequently more versatile functionality, which require further research.

4. Conclusion and Perspectives In summary, biomolecules possess unique properties which allow the development biomimetic functional nanomaterials suitable for a wide range of biomedical applications from sensing, imaging, delivery to therapy. Their distinctive features enable them to either act as a template in facilitating the formation of nanomaterials via the “bio-templating” synthesis or self-organize into highly ordered and functional architectures via the “bio-assembling” strategy. In both cases, the formation of higher ordered materials involves the cooperation of multiple intermolecular interactions including non-covalent interactions such as π-π stacking, hydrogen bonding, electrostatic attraction, hydrophobic interaction and van der Waals’ forces. By manipulating their interplay, it could give rise to dynamic and responsive changes, allowing the construction of a multitude of structures and morphologies from 1D, 2D to 3D over a range of 144 Ito et al.; Advances in Bioinspired and Biomedical Materials Volume 2 ACS Symposium Series; American Chemical Society: Washington, DC, 2017.


length scales. Nonetheless, this requires profound and extensive understanding of these bioinspired approaches in the formation of functional nanostructures. This will include the detailed study of effectual self-arrangement of DNAs and peptides into hierarchical complex, and their interactions with other materials to promote growth of nanoparticles. When equipped with this knowledge, the future of this field would be expected to expand towards more complex and responsive structures that closely mimics the biological system. The recent successes in the design of complex nanostructures based on DNAs and peptides have demonstrated great promises of bio-templating and bio-assembly approaches to engineer next generation functional biomimetic nanomaterials for more advanced biomedical applications such theranostic and nanorobotics for surgery.

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