非典型核酸结构的荧光点亮成像检测

doi:10.6023/cjoc202503034

摘要/Abstract

相比于经典的单链和双链型经典核酸结构, 非典型核酸结构(如G4s、i-motif、Triplex及环形核酸)因其被发现的重要生物功能和在生理环境下的动态平衡异常与多种重大疾病的密切关联性而逐渐成为生物医学研究的热点. 传统凝胶电泳、核磁共振、圆二色性检测技术存在空间分辨率低、破坏性大、缺乏实时动态监测能力等不足. 近年来, 荧光探针材料因其高灵敏度、快速响应性以及动态实时观测性能等逐渐成为非经典核酸结构检测的前沿工具. 综述了非经典核酸结构的荧光点亮材料, 包括传统荧光小分子、聚集诱导发光原(AIEgens)等, 并详述了设计原理、检测机制及应用场景. 当前探针技术通过优化分子构效关系提升识别性与信噪比, 但仍面临选择性不足、活体穿透性差等挑战. 未来需融合多模态成像、人工智能辅助设计及靶向递送系统, 构建高灵敏、多通道响应的检测平台, 以解析核酸动态构象与疾病关联性, 推动开发精准诊断与新型治疗策略.

关键词: 非典型核酸结构, G-四聚体(G4s), 荧光探针, 选择性识别, 高灵敏, 聚集诱导发光(AIE), 精准医疗

Compared to the single-stranded and double-stranded types of classical nucleic acid structures, atypical nucleic acid structures (such as G4s, i-motif, Triplex, and cyclic nucleic acids) are gradually becoming hotspots in biomedical research due to their important biological functions and the close correlation between their abnormal dynamics equilibrium in physiological environments and a variety of hard-tackle diseases. The traditional gel electrophoresis, nuclear magnetic resonance, and circular dichroism detection techniques have shortcomings such as low spatial resolution, high destructiveness, and lack of real-time dynamic monitoring capability. In recent years, fluorescence imaging has gradually become a cutting-edge tool for non-classical nucleic acid structure detection due to their high sensitivity, fast response and dynamic real-time observation performance. In this contribution, we review the fluorescence materials for lighting-up imaging of non-classical nucleic acid structures, including traditional fluorescent small molecules and aggregation-induced emission luminogens (AIEgens). The design principles, detection mechanisms and application scenarios are detailed. Current fluorescence probes have already improved qualities in recognition targetability and signal-to-noise ratio by tuning and optimizing molecular structure-property relationships, but still face challenges such as insufficient selectivity and poor penetration capability in vivo. In the future, it is necessary to integrate multimodal imaging, artificial intelligence-assisted design and targeted delivery system to build a highly sensitive and multi-channel responsive platform to thoroughly disclose the association between the dynamic conformation of nucleic acid and disease, and to promote the development of precise and novel therapeutic strategies.

Key words: atypical nucleic acid structure, G-quadruplexes (G4s), fluorescence probe, selective recognition, high sensitivity, aggregation-induced emission (AIE), precise medicine

引用此文

陈冰燕, 孙洁, 熊玲红, 何学文. 非典型核酸结构的荧光点亮成像检测[J]. 有机化学, 2025, 45(11): 4082-4107.

Bingyan Chen, Jie Sun, Linghong Xiong, Xuewen He. Fluorescence Light-Up Detection and Imaging of Atypical Nucleic Acid Structures[J]. Chinese Journal of Organic Chemistry, 2025, 45(11): 4082-4107.

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图/表 34

Figure 1. (a) Structures of common cyanine dyes; (b) Highly selective disaggregation induced luminescence of parallel G4s by CSTS (a) Reproduced from [40], Copy right 2021 Frontiers; (b) Reproduced from [42], Copy right 2014 American Chemical Society.

Figure 2. Structural differences (a) and fluorescence properties (b) between QCy(MeBT)3 and QCy(BnBT)3 Reproduced from [43]. Copy right 2023 American Chemical Society.

Figure 3. (a) Structural formula of SCY-5; (b) Luminescence phenomenon of SCY-5 inducing the disassembly of parallel G4s upon binding; (c) Fluorescence intensity (F/F0) of SCY-5 at 590 nm in the presence of different nucleic acid models Reproduced from [44]. Copy right 2024 American Chemical Society.

Figure 4. (a) Combination of SN-Cy5-S monomer with G4s inhibited twisted intramolecular charge transfer (TICT) and turn-on fluorescence; (b) Fluorescence enhancement (F/F0) of SN-Cy5-S after interaction with different nucleic acids; (c) Confocal fluorescence image of SN-Cy5-S mitochondrial co-localization Reproduced from [45]. Copy right 2023 American Chemical Society.

Figure 5. TO bind and distinguish Triplex and G4s with high affinity Reproduced from [47]. Copy right 2010 American Chemical Society.

Figure 6. (a) Schematic diagram of the combination of TOVJ and G4s; (b) Confocal fluorescence images of HeLa cells stained with TOVJ and Mito Deep Red Reproduced from [48]. Copy right 2021 American Chemical Society.

Figure 7. (a) Schematic diagram of the structure of TOR-G4; (b) Emission spectra of TOR-G4 in complex with different nucleic acids; (c) Confocal and FLIM images of TOR-G4 in U2OS cells Reproduced from [49]. Copy right 2023 American Chemical Society.

Figure 8. Schematic diagram of the principle of ThT determination of G4s Reproduced from [50]. Copy right 2014 Oxford University Press.

Figure 9. (a) Schematic diagram of the selective binding of IMT and G4s; (b) Relationship between F/F0 after the combination of IMT and c-kit and the concentration of IMT; (c) Confocal imaging of Hela cells stained and fixed with IMT and PI Reproduced from [51]. Copy right 2018 Oxford University Press.

Figure 10. (a) Schematic diagram of the principle of detecting HCV vRNA using G4s probe ThT-NE; (b) Fluorescence spectra of ThT-NE in the presence of CG2a and direct intracellular visualization of CG2a by this probe; (c) Molecular structure, probe properties and modification of ThT; (d) Differentiation of cell cycle by ThT-NA through RNA G4 formation signal (a, b) Reproduced from [52], Copy right 2019 American Chemical Society.; (c, d) Reproduced from [53], Copy right 2022 American Chemical Society.

Figure 11. (a) Schematic diagram of the principle of G4s detection by NIRG-2; (b) Imaging images of lymph node metastatic tumors using NIRG-2 Reproduced from [54]. Copy right 2024 American Chemical Society.

Figure 12. Schematic diagram of CQ4 selective detection and parallel G4s, as well as the confocal fluorescence images of HeLa cells stained and fixed with CQ4 and Hoechst 33342 Reproduced from [55]. Copy right 2020 Wiley Online Library.

Figure 13. Schematic diagram of P0 detecting G4s in the presence of K＋ and fluorescence enhancement ratio of P0 after binding to G4s Reproduced from [56]. Copy right 2024 American Chemical Society.

Figure 14. (a) Structural formula of SiR-PyPDS; (b) Schematic diagram of single-molecule fluorescence imaging of SiR-PyPDS for G4 MYC and mutant MYC (Mut) Reproduced from [57]. Copy right 2020 Springer Nature.

Figure 15. Contour plots and color-coded images of single attenuation fitting for DAOTA-M2 Reproduced from [58]. Copy right 2015 Springer Nature.

Figure 16. Imaging of G4s in living cells by SG4 nano-antibodies Reproduced from [59]. Copy right 2022 American Chemical Society.

Figure 17. (a) Schematic diagram of the mechanism by which the peptide-based fluorescent probe CV2 illuminates G4; (b) Imaging of CV2 monitoring mitochondrial DNA damage in cancer cells. Reproduced from [60]. Copy right 2023 Wiley Online Library.

Figure 18. Colistin COL selectively induced parallel G4s aggregation Reproduced from [61]. Copy right 2025 American Chemical Society.

Figure 19. Schematic diagram of the mechanism of TTAPE detection of G4s formation.

Figure 20. (a) Schematic diagram of the structure of PZ-1; (b) Fluorescence and absorption spectra of PZ-1 binding with G4s Reproduced from [85]. Copy right 2021 Elsevier.

Figure 21. (a) Schematic diagram of the mechanism of TPE-mTO for detecting G4 structures; (b) Confocal fluorescence images of TPE-mTO used in A549 cells Reproduced from [86]. Copy right 2020 Elsevier.

Figure 22. (a) Schematic diagram of the mechanism of G4 detection by TPA-mTO; (b) Confocal imaging of TPA-mTO in A549 cells Reproduced from [87]. Copy right 2024 Wiley Online Library.

Figure 23. (a) Schematic diagram of HMPQ for selective imaging of G4s; (b) Confocal images of HeLa cells treated with HMPQ and G4s detected by the G4 structure-specific antibody BG4. Reproduced from [88]. Copy right 2024 Elsevier.

Figure 24. (a) Structurs of benzothiazolinone coumarin derivatives 5i and 5c; (b) Steady-state fluorescence emission spectra of 5i and 5c in combination with different i-motifs Reproduced from [93]. Copy right 2025 Elsevier.

Figure 25. (a) Schematic diagram of the structure of G59; (b) Fluorescence emission spectra of G59 after adding different concentrations of i-motif; (c) Fluorescence changes of G59 binding with i-motif containing c-MYC promoter and other DNA Reproduced from [94]. Copy right 2022 MDPI.

Figure 26. (a) Structurs of [Ru(bqp)2]2＋; (b) Normalized emission intensities of cis,trans in the absence of DNA (black), hTeloC (green), DAP (blue), DS (red), and hTeloG (pink); (c) Fluorescence lifetimes of cis, trans and monomers under different conditions Reproduced from [95]. Copy right 2020 American Chemical Society.

Figure 27. (a) Schematic diagram of the structure of Hyp; (b) Hyp distinguishes i-motif structures of different lengths through fluorescence intensity Reproduced from [97]. Copy right 2022 American Chemical Society.

Figure 28. (a) Schematic diagram of Triplex detection mechanism of NIAD-4 and adenosine triphosphate (ATP) sensor based on Triplex; (b) FIS combined with Triplex to trigger ESIPT process to turn on fluorescence. (a) Reproduced from [100]. Copy right 2023 American Chemical Society; (b) Reproduced from [101]. Copy right 2015 American Chemical Society.

Figure 29. Sensing technology based on HCR amplification and Triplex assembly Reproduced from [102]. Copy right 2018 Elsevier.

Figure 30. AgNCs binding to Triplex and PH-regulated fluore- scence Reproduced from [103]. Copy right 2022 American Chemical Society

Figure 31. Schematic diagram of the construction of gene-encoded luminescent RNA aptamers for sensitive and marker-free detection of circMTO1 Reproduced from [104]. Copy right 2023 American Chemical Society.

Figure 32. High-resolution visualization of mtDNA in living cells by LC Reproduced from [106]. Copy right 2018 The Royal Society of Chemistry.

Figure 33. YON assesses cellular health in real time by monitoring changes in mtDNA Reproduced from [107]. Copy right 2022 American Chemical Society.

Probe	Types of nucleic acid	Key features	Ref.
CSTS	G4s	Disaggregation-Induced Emission (DIE), V-shaped rigid plane π bracket combined with the parallel G4s through the	[42]
QCy(BnBT)₃	G4s	High specificity recognition of G4s and 500 times fluorescence enhancement	[43]
SCY-5	G4s	J-Aggregates dissociate into monomers, high specificity recognition of parallel G4s	[44]
SN-Cy5-S	G4s	Disaggregation-Induced Emission (DIE), Y-shaped plane is combined with the top plane at the 5' end of G4s	[45]
TO	G4s and Triplex	Distinguish between Triplex and G4s, strong fluorescence enhancement	[47]
TOVJ	G4s	High specificity recognition of antiparallel G4s, near-infrared emission	[48]
TOR-G4	G4s	Two-photon excitation, fluorescence lifetime has increased significantly	[49]
ThT	G4s	High cell membrane permeability, specific recognition ability for G4s	[50]
IMT	G4s	Stack on the 3'-G4 end plane, low background and high signal-to-noise ratio emissions	[51]
ThT-NE	G4s	Intramolecular rotation is restricted and fluorescence is activated, high selectivity and sensitivity	[52]
ThT-NA	G4s	Red light emission, large Stokes shift, high fluorescence turn-on ratio and high selectivity for G4s	[53]
NIRG-2	G4s	Near-infrared Region II emission, hydrogen bonds and π-π stacking combine with G4s	[54]
CQ4	G4s	Disaggregation-Induced Emission (DIE), specifically bind parallel G4s	[55]
P0	G4s	The dimer G4/P0 system carried out highly selective detection of K^＋	[56]
SiR-PyPDS	G4s	The G4s ligand Pyridostatin (PyPDS) forms hydrogen bonds and hydrophobic interactions to specifically bind to G4s	[57]
DAOTA-M2	G4s	G4s were identified by fluorescence lifetime imaging microscopy (FLIM) technology	[58]
SG4	G4s	Antibodies against the structure of human c-MYC G4, bind to green fluorescent protein (GFP)	[59]
CV2	G4s	Peptide sequences specifically recognizing G4s (L-ARG-L-Gli-glutaric acid), Imaging of mitochondrial G4s	[60]
COL	G4s	Induce parallel G4s to aggregate from the nucleic acid mixture	[61]
TTAPE	G4s	Aggregation-induced emission detection (AIE), real-time monitoring of the folding process of G-rich DNA strands to form G4s	[84]
PZ-1	G4s	Aggregation-induced emission detection (AIE), G4s is combined through electrostatic interaction and π-π stacking	[85]
TPE-mTO	G4s	Electron-deficient cation conjugated systems and crescent-shaped scaffolds, specifically locate G4s in mitochondria	[86]
TPA-mTO	G4s	Near-infrared emission, ideal photostability, and high fluorescence contras	[87]
HMPQ	G4s	AIEgens of biological origin, the π-π interaction binds to G4s, high selectivity and high sensitivity	[88]
5i and 5c	i-motif	Combining different types of I-motifs, the fluorescence intensity is enhanced and the fluorescence lifetime is increased	[93]
G59	i-motif	Specifically recognize and visually detect the i-motif structure of the c-MYC gene promoter	[94]
[Ru(bqp)₂]^2＋	i-motif	The cis isomer combines with the DAP i-motif, resulting in fluorescence activation and increased fluorescence lifetime	[95]
Hyp	i-motif	The i-motif structures of different lengths were distinguished by fluorescence intensity	[97]
NIAD-4	Triplex	Uncharged near-infrared molecular rotor probe, topological match with the Triplex terminal triad	[100]
FIS	Triplex	The quantity ratio of 2∶1 is combined with Triplex, the ESIPT process is triggered and the green fluorescence lights up	[101]
Berberine	Triplex	Isoquinoline alkaloids, combined with the Triplex structure, it will show strong fluorescence at 530 nm	[102]
AgNCs	Triplex	The dynamic changes of photophysical properties with the Triplex structure	[103]
DFHBI	circRNA	Using circMTO1 as the template, the aptamers generated by RPA and transcriptional amplification techniques were combined with DFHBI	[104]
LC	circDNA	Efficient intracellular uptake capacity, high-resolution visual imaging detection of mitochondrial DNA (mtDNA)	[106]
YON	circDNA	Near-infrared twisted intramolecular charge transfer (TICT) fluorescent probe, high sensitivity and large Stokes displacement	[107]

Probe	Types of nucleic acid	Key features	Ref.
CSTS	G4s	Disaggregation-Induced Emission (DIE), V-shaped rigid plane π bracket combined with the parallel G4s through the	[42]
QCy(BnBT)₃	G4s	High specificity recognition of G4s and 500 times fluorescence enhancement	[43]
SCY-5	G4s	J-Aggregates dissociate into monomers, high specificity recognition of parallel G4s	[44]
SN-Cy5-S	G4s	Disaggregation-Induced Emission (DIE), Y-shaped plane is combined with the top plane at the 5' end of G4s	[45]
TO	G4s and Triplex	Distinguish between Triplex and G4s, strong fluorescence enhancement	[47]
TOVJ	G4s	High specificity recognition of antiparallel G4s, near-infrared emission	[48]
TOR-G4	G4s	Two-photon excitation, fluorescence lifetime has increased significantly	[49]
ThT	G4s	High cell membrane permeability, specific recognition ability for G4s	[50]
IMT	G4s	Stack on the 3'-G4 end plane, low background and high signal-to-noise ratio emissions	[51]
ThT-NE	G4s	Intramolecular rotation is restricted and fluorescence is activated, high selectivity and sensitivity	[52]
ThT-NA	G4s	Red light emission, large Stokes shift, high fluorescence turn-on ratio and high selectivity for G4s	[53]
NIRG-2	G4s	Near-infrared Region II emission, hydrogen bonds and π-π stacking combine with G4s	[54]
CQ4	G4s	Disaggregation-Induced Emission (DIE), specifically bind parallel G4s	[55]
P0	G4s	The dimer G4/P0 system carried out highly selective detection of K^＋	[56]
SiR-PyPDS	G4s	The G4s ligand Pyridostatin (PyPDS) forms hydrogen bonds and hydrophobic interactions to specifically bind to G4s	[57]
DAOTA-M2	G4s	G4s were identified by fluorescence lifetime imaging microscopy (FLIM) technology	[58]
SG4	G4s	Antibodies against the structure of human c-MYC G4, bind to green fluorescent protein (GFP)	[59]
CV2	G4s	Peptide sequences specifically recognizing G4s (L-ARG-L-Gli-glutaric acid), Imaging of mitochondrial G4s	[60]
COL	G4s	Induce parallel G4s to aggregate from the nucleic acid mixture	[61]
TTAPE	G4s	Aggregation-induced emission detection (AIE), real-time monitoring of the folding process of G-rich DNA strands to form G4s	[84]
PZ-1	G4s	Aggregation-induced emission detection (AIE), G4s is combined through electrostatic interaction and π-π stacking	[85]
TPE-mTO	G4s	Electron-deficient cation conjugated systems and crescent-shaped scaffolds, specifically locate G4s in mitochondria	[86]
TPA-mTO	G4s	Near-infrared emission, ideal photostability, and high fluorescence contras	[87]
HMPQ	G4s	AIEgens of biological origin, the π-π interaction binds to G4s, high selectivity and high sensitivity	[88]
5i and 5c	i-motif	Combining different types of I-motifs, the fluorescence intensity is enhanced and the fluorescence lifetime is increased	[93]
G59	i-motif	Specifically recognize and visually detect the i-motif structure of the c-MYC gene promoter	[94]
[Ru(bqp)₂]^2＋	i-motif	The cis isomer combines with the DAP i-motif, resulting in fluorescence activation and increased fluorescence lifetime	[95]
Hyp	i-motif	The i-motif structures of different lengths were distinguished by fluorescence intensity	[97]
NIAD-4	Triplex	Uncharged near-infrared molecular rotor probe, topological match with the Triplex terminal triad	[100]
FIS	Triplex	The quantity ratio of 2∶1 is combined with Triplex, the ESIPT process is triggered and the green fluorescence lights up	[101]
Berberine	Triplex	Isoquinoline alkaloids, combined with the Triplex structure, it will show strong fluorescence at 530 nm	[102]
AgNCs	Triplex	The dynamic changes of photophysical properties with the Triplex structure	[103]
DFHBI	circRNA	Using circMTO1 as the template, the aptamers generated by RPA and transcriptional amplification techniques were combined with DFHBI	[104]
LC	circDNA	Efficient intracellular uptake capacity, high-resolution visual imaging detection of mitochondrial DNA (mtDNA)	[106]
YON	circDNA	Near-infrared twisted intramolecular charge transfer (TICT) fluorescent probe, high sensitivity and large Stokes displacement	[107]

Table 1. Comparison of different fluorescent probes for the detection of atypical nucleic acids

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