# Nucleobase-Containing Polymers: Structure, Synthesis, and Applications
## 3 Synthetic Nucleobase-Containing Polymers
### Synthesizing Nucleobase Polymers by Click Chemistry  
\"Click chemistry\" is a concept introduced by [PERSON] [54] in 2001 and since then has become one of the most powerful paradigms in polymer chemistry and materials science [55; 56; 57]. Due to its simplicity and efficiency, click chemistry has been extensively employed for accessing linear  
Figure 4: (**a**) Self-assembly of nucleobase polymer templates into micelles and (**b**) the templated polymerization of complementary nucleobase monomers [28]. Reproduced with permission. Copyright Springer Nature, 2012.  
polymers [58; 59; 60; 61; 62; 63], branched polymers [64; 65; 66; 67; 68; 69; 70; 71; 72; 73], dendrimers [74; 75; 76; 77; 78; 79], and polymer networks [80; 81; 82; 83; 84; 85]. The combination of click chemistry and nucleobase-containing polymers is promising. For example, in 2014 [PERSON] et al. reported a facile and scalable method to synthesize DNA-mimetic sequential polymers with tailored hetero-functional groups based on radical-initiated thiol-yne click polymerization [39]. Firstly, radicals were generated from either a UV or thermal initiator, yielding a thiyl radical, enabled stepwise propagation, and polymer chain transfer (shown in Figure 5). With a delicate selection of monomers with different functionalities, various types of sequenced polymers such as linear sequence, periodic sequence, random sequence, and hyperbranched sequence were obtained (Figure 5). Furthermore, to achieve single-strand DNA-mimetic macromolecules, alternating adenine and thymine groups were introduced by another classic click chemistry: Cu-catalyzed azide and alkyne cycloaddition (CuAAC). This work is an excellent example of utilizing two orthogonal click reactions to synthesize nucleobase-containing polymers from simple starting substrates in two simple steps, indicating the power of click chemistry. In 2015, [PERSON] et al. [38] synthesized nucleobase-containing sequence-controlled polymers (homopolymers of a single nucleobase or homopolymers of specific repeating nucleobase sequences) by combining orthogonal thiol-ene and thiol-Michael click chemistry reactions (Scheme 5) [86; 87; 88; 89]. In this case, a thiol-protected acrylamide monomer is coupled to a functionalized thiol-allylamine monomer in a thiol-Michael addition, then the thiol group is deprotected to restore the thiol and polymerized with allyamine functional groups by radical initiation of the thiol-ene reaction. This \"click\" by \"click\" approach is a great demonstration of synthesizing nucleobase-functionalized sequence-controlled periodic copolymers/oligomers and polymers without the use of a solid support. In addition, these nucleobase-containing polymers were employed in various applications in materials science, such as sequence-controlled assembly of nanoparticles, DNA delivery [90], and organogel formation [91]. **Scheme 5. (A) General monomer structure for thiol-based click polymerization (R represents functional group, including but not limited to nucleobases); (B) The two types of thiol click reaction; (C) Thiol-click reaction strategy for sequence-controlled periodic functional oligomers and polymers [38]. Reproduced with permission. Copyright John Wiley and Sons, 2015. **In 2017, [PERSON] et al. [40] presented a synthesis of an intrinsically water-soluble single-stranded DNA analog formed by the synthesis of a Clickable Nucleic Acid (CNA). They formed molecules with pendant hydroxyl groups present on the main polymer backbone, and subsequent modification of those hydroxyls with sulfonate moieties further enhances the hydrophilicity (Figure 6). The CNA polymer with one pendant hydroxyl group for each dimer was obtained by the radical-mediated thiol-ene polymerization approach. A few simple steps were needed to functionalize the free hydroxyl group on the polymer backbone to obtain the water-soluble CNA polymer. Furthermore, they demonstrated that this water-soluble CNA polymer was capable of binding to complementary DNA on the surface of nanoparticles.