Recent Advances in Small Molecules-mediated DNA Conformations: From Structural Characteristics to Applications

doi:10.1007/s40242-026-6067-3

Abstract

Abstract: In DNA nanotechnology, Watson-Crick-Franklin base-pairing is the dominant interaction driving the formation of various functional platforms, such as DNA origami, hydrogels, machines, condensates, etc. The introduction of noncanonical DNA secondary structures, including i-motif, G-quadruplex, triplex, A-motif, ion-bridged duplex, etc., renders these platforms with the capability to respond to external stimuli (pH, ions, light, etc.), which significantly expands their functionalities in smart response to external circumstances. Besides these, small molecules (or low-molecular-weight cofactors) also induce the transition of specific DNA sequences into noncanonical secondary structures. This review summarizes the recent progress of these small molecules, especially base analogues, including cyanuric acid (CA), melamine, etc., in constructing stimuli-responsive DNA structures and their implementation in various research fields. Their structural characteristics are systematically examined. Examples are also highlighted to showcase the wide applications of using these orthogonal small molecules-mediated DNA structures. A comparison to established methods is illustrated. Moreover, current challenges and future aspects are discussed.

Key words: Cofactor, DNA, Noncanonical, Small molecule

HU Yuwei, NIU Li. Recent Advances in Small Molecules-mediated DNA Conformations: From Structural Characteristics to Applications[J]. Chemical Research in Chinese Universities, 2026, 42(4): 1017-1034.

References

[1] Seeman N. C., J. Theor. Biol., 1982, 99, 237.
[2] Zhang D. Y., Seelig G., Nat. Chem., 2011, 3, 103.
[3] Seeman N. C., Sleiman H. F., Nat. Rev. Mater., 2017, 3, 17068.
[4] Madsen M., Gothelf K. V., Chem. Rev., 2019, 119, 6384.
[5] Li F., Li J., Dong B., Wang F., Fan C., Zuo X., Chem. Soc. Rev., 2021, 50, 5650.
[6] Del Grosso E., Franco E., Prins L. J., Ricci F., Nat. Chem., 2022, 14, 600.
[7] Modi S., M G. S., Goswami D., Gupta G. D., Mayor S., Krishnan Y., Nat. Nanotechnol., 2009, 4, 325.
[8] Farooq M. U., Lawrie C. H., Deng N. N., Adv. Mater., 2025, 37, e2508047.
[9] Li B., Lu Y., Huang X., Sojic N., Jiang D., Liu B., Angew. Chem. Int. Ed., 2025, 64, e202421658.
[10] Zhan P., Peil A., Jiang Q., Wang D., Mousavi S., Xiong Q., Shen Q., Shang Y., Ding B., Lin C., Ke Y., Liu N., Chem. Rev., 2023, 123, 3976.
[11] Hao Y., Kristiansen M., Sha R., Birktoft J. J., Hernandez C., Mao C., Seeman N. C., Nat. Chem., 2017, 9, 824.
[12] Chen C., Wei X., Parsons M. F., Guo J., Banal J. L., Zhao Y., Scott M. N., Schlau-Cohen G. S., Hernandez R., Bathe M., Nat. Commun., 2022, 13, 4935.
[13] Ryssy J., Natarajan A. K., Wang J., Lehtonen A. J., Nguyen M. K., Klajn R., Kuzyk A., Angew. Chem. Int. Ed., 2021, 60, 5859.
[14] Zhao Y., Chandrasekaran A. R., Rusling D. A., Woloszyn K., Hao Y., Hernandez C., Vecchioni S., Ohayon Y. P., Mao C., Seeman N. C., Sha R., J. Am. Chem. Soc., 2023, 145, 3599.
[15] Veneziano R., Ratanalert S., Zhang K., Zhang F., Yan H., Chiu W., Bathe M., Science, 2016, 352, 1534.
[16] Lv H., Xie N., Li M., Dong M., Sun C., Zhang Q., Zhao L., Li J., Zuo X., Chen H., Wang F., Fan C., Nature, 2023, 622, 292.
[17] Hu M., Li X., Wu J. N., Yang M., Wu T., ACS Nano, 2024, 18, 2184.
[18] Xiong X., Xiao M., Lai W., Li L., Fan C., Pei H., Angew. Chem. Int. Ed., 2021, 60, 3397.
[19] Hu Y., Fan C., Chem, 2022, 8, 1554.
[20] Wang J., Li Z., Willner I., Angew. Chem. Int. Ed., 2023, 62, e202215332.
[21] Liu W., Samanta A., Deng J., Akintayo C. O., Walther A., Angew. Chem. Int. Ed., 2022, 61, e202208951.
[22] Chai H. X., Kayanuma K., Suzuki H., Takinoue M., JACS Au, 2025, 5, 3249.
[23] Chen W., Duzs B., Argudo P. G., Bauer S. V., Liu W., Samanta A., Parekh S. H., Bonn M., Walther A., Nat. Nanotechnol., 2025, 20, 1062.
[24] Merindol R., Loescher S., Samanta A., Walther A., Nat. Nanotechnol., 2018, 13, 730.
[25] Samanta A., Sabatino V., Ward T. R., Walther A., Nat. Nanotechnol., 2020, 15, 914.
[26] Wang S., Mao X., Wang F., Zuo X., Fan C., Adv. Mater., 2024, 36, e2307499.
[27] Yang S., Bogels B. W. A., Wang F., Xu C., Dou H., Mann S., Fan C., de Greef T. F. A., Nat. Rev. Chem., 2024, 8, 179.
[28] Liu S., Jiang Q., Zhao X., Zhao R., Wang Y., Wang Y., Liu J., Shang Y., Zhao S., Wu T., Zhang Y., Nie G., Ding B., Nat. Mater., 2021, 20, 421.
[29] Zhu G., Mei L., Vishwasrao H. D., Jacobson O., Wang Z., Liu Y., Yung B. C., Fu X., Jin A., Niu G., Wang Q., Zhang F., Shroff H., Chen X., Nat. Commun., 2017, 8, 1482.
[30] Yao C., Zhu C., Tang J., Ou J., Zhang R., Yang D., J. Am. Chem. Soc., 2021, 143, 19330.
[31] Zheng L. L., Li J. Z., Wen M., Xi D., Zhu Y., Wei Q., Zhang X. B., Ke G., Xia F., Gao Z. F., Sci. Adv., 2023, 9, eadf5868.
[32] Meng H. M., Liu H., Kuai H., Peng R., Mo L., Zhang X. B., Chem. Soc. Rev., 2016, 45, 2583.
[33] Zhou Z., Lin N., Ouyang Y., Liu S., Zhang Y., Willner I., J. Am. Chem. Soc., 2023, 145, 12617.
[34] Zhou Z., Wang J., Willner I., J. Am. Chem. Soc., 2021, 143, 241.
[35] Wang S., Yue L., Li Z. Y., Zhang J., Tian H., Willner I., Angew. Chem. Int. Ed., 2018, 57, 8105.
[36] Ouyang Y., Dong J., Willner I., J. Am. Chem. Soc., 2023, 145, 22135.
[37] Leathers A., Walczak M., Brady R. A., Al Samad A., Kotar J., Booth M. J., Cicuta P., Di Michele L., J. Am. Chem. Soc., 2022, 144, 17468.
[38] Di Antonio M., Ponjavic A., Radzevicius A., Ranasinghe R. T., Catalano M., Zhang X., Shen J., Needham L. M., Lee S. F., Klenerman D., Balasubramanian S., Nat. Chem., 2020, 12, 832.
[39] Zyner K. G., Simeone A., Flynn S. M., Doyle C., Marsico G., Adhikari S., Portella G., Tannahill D., Balasubramanian S., Nat. Commun., 2022, 13, 142.
[40] Monsen R. C., Trent J. O., Chaires J. B., Acc. Chem. Res., 2022, 55, 3242.
[41] Zeraati M., Langley D. B., Schofield P., Moye A. L., Rouet R., Hughes W. E., Bryan T. M., Dinger M. E., Christ D., Nat. Chem., 2018, 10, 631.
[42] Li T., Famulok M., J. Am. Chem. Soc., 2013, 135, 1593.
[43] Liu H., Xu Y., Li F., Yang Y., Wang W., Song Y., Liu D., Angew. Chem. Int. Ed., 2007, 46, 2515.
[44] Hu Y., Cecconello A., Idili A., Ricci F., Willner I., Angew. Chem. Int. Ed., 2017, 56, 15210.
[45] Chen F., Lu Q., Huang L., Liu B., Liu M., Zhang Y., Liu J., Angew. Chem. Int. Ed., 2021, 60, 5453.
[46] Tang Q., Lai W., Wang P., Xiong X., Xiao M., Li L., Fan C., Pei H., Angew. Chem. Int. Ed., 2021, 60, 15013.
[47] Jiang Q., Xu X., Yin P. A., Ma K., Zhen Y., Duan P., Peng Q., Chen W. Q., Ding B., J. Am. Chem. Soc., 2019, 141, 9490.
[48] Chakraborty S., Sharma S., Maiti P. K., Krishnan Y., Nucleic Acids Res., 2009, 37, 2810.
[49] Hu Y., Ying J. Y., Mater. Today, 2023, 63, 188.
[50] Kondo J., Tada Y., Dairaku T., Hattori Y., Saneyoshi H., Ono A., Tanaka Y., Nat. Chem., 2017, 9, 956.
[51] Kratochvilova I., Golan M., Vala M., Sperova M., Weiter M., Pav O., Sebera J., Rosenberg I., Sychrovsky V., Tanaka Y., Bickelhaupt F. M., J. Phys. Chem. B, 2014, 118, 5374.
[52] Hu Y., Gao S., Lu H., Ying J. Y., J. Am. Chem. Soc., 2022, 144, 5461.
[53] Hu Y., Guo W., Kahn J. S., Aleman-Garcia M. A., Willner I., Angew. Chem. Int. Ed., 2016, 55, 4210.
[54] Cheng E., Xing Y., Chen P., Yang Y., Sun Y., Zhou D., Xu L., Fan Q., Liu D., Angew. Chem. Int. Ed., 2009, 48, 7660.
[55] Guo W., Lu C. H., Qi X. J., Orbach R., Fadeev M., Yang H. H., Willner I., Angew. Chem. Int. Ed., 2014, 53, 10134.
[56] Hu Y., Gao S., Lu H., Tan S., Chen F., Ke Y., Ying J. Y., Nano Lett., 2023, 23, 9778.
[57] Yu X., Hu Y., Kahn J. S., Cecconello A., Willner I., Chem. Eur. J., 2016, 22, 14504.
[58] Fischer A., Lilienthal S., Vazquez-Gonzalez M., Fadeev M., Sohn Y. S., Nechushtai R., Willner I., J. Am. Chem. Soc., 2020, 142, 4223.
[59] Huang F., Liao W. C., Sohn Y. S., Nechushtai R., Lu C. H., Willner I., J. Am. Chem. Soc., 2016, 138, 8936.
[60] Kuzyk A., Urban M. J., Idili A., Ricci F., Liu N., Sci. Adv., 2017, 3, e1602803.
[61] Ranallo S., Prevost-Tremblay C., Idili A., Vallee-Belisle A., Ricci F., Nat. Commun., 2017, 8, 15150.
[62] Debnath M., Fatma K., Dash J., Angew. Chem. Int. Ed., 2019, 58, 2942.
[63] Dong Y., Yang Z., Liu D., Acc. Chem. Res., 2014, 47, 1853.
[64] Dong J., O'Hagan M. P., Willner I., Chem. Soc. Rev., 2022, 51, 7631.
[65] Moser H. E., Dervan P. B., Science, 1987, 238, 645.
[66] Beal P. A., Dervan P. B., Science, 1991, 251, 1360.
[67] Schuster G. B., Hud N. V., Alenaizan A., J. Phys. Chem. B, 2022, 126, 10758.
[68] Avakyan N., Greschner A. A., Aldaye F., Serpell C. J., Toader V., Petitjean A., Sleiman H. F., Nat. Chem., 2016, 8, 368.
[69] Li Q., Zhao J., Liu L., Jonchhe S., Rizzuto F. J., Mandal S., He H., Wei S., Sleiman H. F., Mao H., Mao C., Nat. Mater., 2020, 19, 1012.
[70] Alenaizan A., J. Phys. Chem. B, 2022, 126, 6948.
[71] Rizzuto F. J., Platnich C. M., Luo X., Shen Y., Dore M. D., Lachance-Brais C., Guarne A., Cosa G., Sleiman H. F., Nat. Chem., 2021, 13, 843.
[72] Lachance-Brais C., Rammal M., Asohan J., Katolik A., Luo X., Saliba D., Jonderian A., Damha M. J., Harrington M. J., Sleiman H. F., Adv. Sci., 2023, 10, e2205713.
[73] Lee S. R., Ong C. Y. J., Wong J. Y., Ke Y., Dong Z., Lim J. Y. C., Hu Y., Chem. Eng. J., 2024, 497, 154698.
[74] Xu S., Ouyang Y., Qin Y., Chen D., Duan Z., Song D., Harries D., Xia F., Willner I., Huang F., Nat. Commun., 2025, 16, 3352.
[75] Hu Y., Liu J., Ke Y., Wang B., Lim J. Y. C., Dong Z., Long Y., Willner I., ACS Appl. Mater. Interfaces, 2024, 16, 29235.
[76] Set C. T., Whitesides G. M., J. Am. Chem. Soc., 1993, 115, 905.
[77] Wu J. X., Bag P. P., Xu Y. T., Gong L., He C. T., Chen X. M., Zhang J. P., Adv. Mater., 2021, 33, 2007368.
[78] Jun Y. S., Lee E. Z., Wang X., Hong W. H., Stucky G. D., Thomas A., Adv. Funct. Mater., 2013, 23, 3661.
[79] Niu H., Zhao W., Lv H., Yang Y., Cai Y., Chem. Eng. J., 2021, 411.
[80] Alenaizan A., Fauche K., Krishnamurthy R., Sherrill C. D., Chem. Eur. J., 2021, 27, 4043.
[81] Kashida H., Hattori Y., Tazoe K., Inoue T., Nishikawa K., Ishii K., Uchiyama S., Yamashita H., Abe M., Kamiya Y., Asanuma H., J. Am. Chem. Soc., 2018, 140, 8456.
[82] Hong F., Zhang F., Liu Y., Yan H., Chem. Rev., 2017, 117, 12584.
[83] Kundu P. K., Samanta D., Leizrowice R., Margulis B., Zhao H., Borner M., Udayabhaskararao T., Manna D., Klajn R., Nat. Chem., 2015, 7, 646.
[84] Shi Z., Peng P., Strohecker D., Liao Y., J. Am. Chem. Soc., 2011, 133, 14699.
[85] Lachance-Brais C., Hennecker C. D., Alenaizan A., Luo X., Toader V., Taing M., Sherrill C. D., Mittermaier A. K., Sleiman H. F., J. Am. Chem. Soc., 2021, 143, 19824.
[86] Lu C. H., Guo W., Hu Y., Qi X. J., Willner I., J. Am. Chem. Soc., 2015, 137, 15723.
[87] Hu Y., Ying J. Y., Small, 2023, 19, e2205909.
[88] Zhao L., Li L., Yang G., Wei B., Ma Y., Qu F., Biosens. Bioelectron., 2021, 194, 113597.
[89] Kahn J. S., Hu Y., Willner I., Acc. Chem. Res., 2017, 50, 680.
[90] Shao Y., Jia H., Cao T., Liu D., Acc. Chem. Res., 2017, 50, 659.
[91] Li Y., Chen R., Zhou B., Dong Y., Liu D., Adv. Mater., 2024, 36, e2307129.
[92] Cangialosi A., Yoon C., Liu J., Huang Q., Guo J., Nguyen T. D., Gracias D. H., Schulman R., Science, 2017, 357, 1126.
[93] Li J., Mo L., Lu C. H., Fu T., Yang H. H., Tan W., Chem. Soc. Rev., 2016, 45, 1410.
[94] English M. A., Soenksen L. R., Gayet R. V., de Puig H., AngenentMari N. M., Mao A. S., Nguyen P. Q., Collins J. J., Science, 2019, 365, 780.
[95] Li F., Lyu D., Liu S., Guo W., Adv. Mater., 2020, 32, e1806538.
[96] Li F., Tang J., Geng J., Luo D., Yang D., Prog. Polym. Sci., 2019, 98, 101163.
[97] He M., Nandu N., Uyar T. B., Royzen M., Yigit M. V., Chem. Commun., 2020, 56, 7313.
[98] Hu Y., Ke Y., Willner I., Adv. Funct. Mater., 2023, 33, 2304966.
[99] Lim A. Z. T., Ho M. S. M., Ke Y., Loh W. W., Dong Z., Wang F., Lim J. Y. C., Zheng X. T., Yang L., Hu Y., Soft Matter., 2025, 21, 3393.
[100] Sontakke V. A., Yokobayashi Y., J. Am. Chem. Soc., 2022, 144, 2149.
[101] Qi H., Ghodousi M., Du Y., Grun C., Bae H., Yin P., Khademhosseini A., Nat. Commun., 2013, 4, 2275.
[102] Lachance-Brais C., Yao C., Reyes-Valenzuela A., Asohan J., Guettler E., Sleiman H. F., J. Am. Chem. Soc., 2024, 146, 5811.
[103] Jiang W., Wu Z., Gao Z., Wan M., Zhou M., Mao C., Shen J., ACS Nano, 2022, 16, 15705.
[104] Andre A. A. M., Spruijt E., Int. J. Mol. Sci., 2020, 21, 5908.
[105] Wang F., Altschuh P., Ratke L., Zhang H., Selzer M., Nestler B., Adv. Mater., 2019, 31, e1806733.
[106] Maruyama T., Gong J., Takinoue M., Nat. Commun., 2024, 15, 7397.
[107] Zeng Y., Pratumyot Y., Piao X., Bong D., J. Am. Chem. Soc., 2012, 134, 832.
[108] Piao X., Xia X., Bong D., Biochemistry, 2013, 52, 6313.
[109] Munyaradzi O., Rundell S., Bong D., ChemBioChem, 2022, 23, e202100707.
[110] Mao J., DeSantis C., Bong D., J. Am. Chem. Soc., 2017, 139, 9815.
[111] Liu S., Li J., Wang Y., Zhang Z., Wang Y., Wang L., Wang L., Small Methods, 2025, 9, e01445.
[112] Shalileh F., Sabahi H., Golbashy M., Dadmehr M., Hosseini M., Microchem. J., 2023, 195, 109316.
[113] Su R., Zheng H., Dong S., Sun R., Qiao S., Sun H., Ma X., Zhang T., Sun C., Anal. Bioanal. Chem., 2019, 411, 2521.
[114] Ying Y.-L., Hu Z.-L., Zhang S., Qing Y., Fragasso A., Maglia G., Meller A., Bayley H., Dekker C., Long Y.-T., Nat. Nanotechnol., 2022, 17, 1136.
[115] Liu L., Wu H. C., Angew. Chem. Int. Ed., 2016, 55, 15216.
[116] Dorey A., Howorka S., Nat. Chem., 2024, 16, 314.
[117] Ho M. S. M., Lim A. Z. T., Ke Y., Loh W. W., Zheng X. T., Yang L., Dong Z., Wang F., Lim J. Y. C., Hu Y., ACS Appl. Mater. Interfaces, 2025, 17, 27116.
[118] Wu L., Wang Y., Xu X., Liu Y., Lin B., Zhang M., Zhang J., Wan S., Yang C., Tan W., Chem. Rev., 2021, 121, 12035.
[119] Liu Z., Robinson J. T., Sun X., Dai H., J. Am. Chem. Soc., 2008, 130, 10876.
[120] Wang A., Yang T., Fan W., Yang Y., Zhu Q., Guo S., Zhu C., Yuan Y., Zhang T., Gan Y., Adv. Healthc. Mater., 2019, 8, e1801123.
[121] Feng X., Wang X., Liu J., Fu A., Wang Y., Wei S., Chen H., She R., Wang Y., Cui X., Hou H., Xu Y., Wu Y., Meng Q., Zhang L., Wang S., Zhao J., Angew. Chem. Int. Ed., 2024, 63,