Carbon monoxide-triggered near-infrared photoacoustic-fluorescent integrated visualization tool for auxiliary diagnosis of heart failure and evaluation of reversal drug efficacy

Abstract

Heart failure (HF), a major global health challenge with high morbidity and mortality, lacks effective biomarkers and non-invasive tools for early diagnosis and therapy evaluation. Endogenous carbon monoxide (CO), a key biological signaling molecule, is closely linked to cardiovascular diseases such as HF when dysregulated. Integrating near-infrared (NIR) fluorescence (FL) imaging with photoacoustic (PA) imaging offers a powerful approach, as the 2D FL data can validate and supplement the 3D PA information for a more holistic disease assessment. Herein, we developed CS-CO, an activatable dual-mode NIR probe for the selective monitoring of CO fluctuations in HF. Density functional theory (DFT) calculations validated the design, elucidating the signal turn-on mechanism upon CO binding. The metal-free CS-CO probe selectively detects CO, resulting in activated NIR absorption (710 nm) and emission (742 nm). Consequently, its excellent NIR PA and FL performance allowed for visualizing both exogenous and endogenous CO in cells, and for 2D FL and 3D PA imaging in mice. Crucially, using this dual-mode imaging approach, CS-CO successfully revealed dynamic CO level changes during both HF progression and drug-induced reversal for the first time. This study provides a pioneering strategy for early HF diagnosis and drug efficacy evaluation, with significant potential clinical impact.

Keywords

carbon monoxide / fluorescent imaging / heart failure / photoacoustic imaging / reversal of heart failure

References

[1] J. R. Zierath, J. van der Velden, A. Javaheri, A. Rosenzweig, D. M. Muoio, E. E. Mulvihill, T. A. Martino, A. Rasheed, X. W. Chen, Z. P. Arany, Cell 2024, 187, 3880.

[2] G. Savarese, P. M. Becher, L. H. Lund, P. Seferovic, G. M. C. Rosano, A. J. S. Coats, Cardiovasc. Res. 2022, 118, 3272.

[3] J. R. Baman, F. S. Ahmad, JAMA, J. Am. Med. Assoc. 2020, 324, 1015.

[4] S. Emmons-Bell, C. Johnson, G. Roth, Heart 2022, 108, 1351.

[5] M. Adamo, R. S. Gardner, T. A. McDonagh, M. Metra, Eur. Heart J. 2022, 43, 440.

[6] J. R. Teerlink, R. Diaz, G. M. Felker, J. J. V. McMurray, M. Metra, S. D. Solomon, K. F. Adams, I. Anand, A. Arias-Mendoza, T. Biering-Sørensen, M. Böhm, D. Bonderman, J. G. F. Cleland, R. Corbalan, M. G. Crespo-Leiro, U. Dahlström, L. E. Echeverria, J. C. Fang, G. Filippatos, C. Fonseca, E. Goncalvesova, A. R. Goudev, J. G. Howlett, D. E. Lanfear, J. Li, M. Lund, P. Macdonald, V. Mareev, S. Momomura, E. O’Meara, A. Parkhomenko, P. Ponikowski, F. J. A. Ramires, P. Serpytis, K. Sliwa, J. Spinar, T. M. Suter, J. Tomcsanyi, H. Vandekerckhove, D. Vinereanu, A. A. Voors, M. B. Yilmaz, F. Zannad, L. Sharpsten, J. C. Legg, C. Varin, N. Honarpour, S. A. Abbasi, F. I. Malik, C. E. Kurtz, N. Engl. J. Med. 2021, 384, 105.

[7] E. Arrigo, S. Comità, P. Pagliaro, C. Penna, D. Mancardi, Int. J. Mol. Sci. 2023, 24, 12480.

[8] A. Katsnelson, ACS Cent. Sci. 2019, 5, 1632.

[9] Y. Xu, L. Wang, L. Yang, R. Xue, H. Zhu, Q. Liu, X. Lv, R. Zhang, J. Tu, Q. Zang, Y. Wang, Chin. Chem. Lett. 2025, 36, 110958.

[10] X. Yang, W. Lu, C. P. Hopper, B. Ke, B. Wang, Acta Pharm. Sin. B 2021, 11, 1434.

[11] C. Cardoso-Pires, H. L. A. Vieira, Biochim. Biophys. Acta, Mol. Basis Dis. 2024, 1870, 167446.

[12] L. M. Chu, S. Shaefi, J. D. Byrne, R. W. Alves de Souza, L. E. Otterbein, Redox Biol. 2021, 48, 102183.

[13] W. L. Reis, V. C. Biancardi, Y. Zhou, J. E. Stern, Endocrinology 2016, 157, 2052.

[14] C. Maack, Nat. Rev. Cardiol. 2025, 22, 695.

[15] J. Li, D. Ding, J. Wang, L. Huang, J. Zhan, W. Lin, Sens. Actuators, B 2022, 367, 132097.

[16] L. Lin, Z. Ba, H. Tian, H. Qin, X. Chen, X. Zhou, S. Zhao, L. Li, F. Xue, H. Li, L. He, X. Li, J. Du, Z. Zhou, W. Zeng, Nat. Commun. 2024, 15, 6610.

[17] J. Du, S. Yang, Y. Qiao, H. Lu, H. Dong, Biosens. Bioelectron. 2021, 191, 113478.

[18] L. D. Adair, K. Yang, E. J. New, Mol. Fluoresc. Sens. Cell. Stud. 2022, 1.

[19] J. Li, D. Ding, J. Wang, L. Xu, D. Tan, W. Lin, Chem. Eng. J. 2022, 448, 137634.

[20] S. J. Sahl, J. Matthias, K. Inamdar, M. Weber, T. A. Khan, C. Brüser, S. Jakobs, S. Becker, C. Griesinger, J. Broichhagen, S. W. Hell, Science 2024, 386, 180.

[21] L. N. Zhang, X. Y. Ran, L. Shi, N. Wang, S. Y. Chen, X. Q. Yu, K. Li, Biosens. Bioelectron. 2025, 289, 117861.

[22] J. Zhou, B. Feng, C. Li, F. Chu, Y. Mo, M. Lin, Y. Zhao, J. Zhou, X. Deng, Q. Meng, J. Huang, H. Zhang, X. Feng, W. Zeng, Biosens. Bioelectron. 2025, 289, 117862.

[23] C. Yan, C. Liu, B. Liu, Q. Zheng, X. Zhao, S. Lu, X. Fu, W. Li, J. Li, D. Li, Y. Yao, Y. Zhang, H. Zhu, P. Shi, W.-H. Zhu, Z. Guo, Nat. Aging 2025, 5, 2532.

[24] X. Fu, Y. Yao, Q. Liu, Z. Guo, C. Yan, W.-H. Zhu, Sci. China:Chem. 2025, 68, 4497.

[25] J. Li, H. Chi, Y. Wu, K. Peng, J. Wang, W. Lin, J. Hazard. Mater. 2024, 473, 134685.

[26] G. Hong, A. L. Antaris, H. Dai, Nat. Biomed. Eng. 2017, 1, 0010.

[27] J. Bin Li, H. W. Liu, T. Fu, R. Wang, X. B. Zhang, W. Tan, Trends Chem. 2019, 1, 224.

[28] L. Chen, Y. Lyu, X. Zhang, L. Zheng, Q. Li, D. Ding, F. Chen, Y. Liu, W. Li, Y. Zhang, Q. Huang, Z. Wang, T. Xie, Q. Zhang, Y. Sima, K. Li, S. Xu, T. Ren, M. Xiong, Y. Wu, J. Song, L. Yuan, H. Yang, X. B. Zhang, W. Tan, Sci. China:Chem. 2023, 66, 1336.

[29] J. Li, J. Wang, L. Xu, H. Chi, X. Liang, J. Yoon, W. Lin, Angew. Chem., Int. Ed. 2024, 63, e202312632.

[30] Y. Tang, Y. Ma, J. Yin, W. Lin, Chem. Soc. Rev. 2019, 48, 4036.

[31] L. Yan, H. Yang, S. Zhang, C. Zhou, C. Lei, Crit. Rev. Anal. Chem. 2023, 53, 1792.

[32] G. Ma, Q. Ding, Y. Zhang, Y. Wang, J. Xiang, M. Li, Q. Zhao, S. Huang, P. Gong, J. S. Kim, Chin. Chem. Lett. 2024, 35, 109293.

[33] M. Liu, B. Feng, F. Chu, D. Fan, F. Zheng, F. Chen, W. Zeng, Chin. Chem. Lett. 2025, 36, 110043.

[34] X. Liu, N. Li, M. Li, H. Chen, N. Zhang, Y. Wang, K. Zheng, Coord. Chem. Rev. 2020, 404, 213109.

[35] L. Yuan, W. Lin, Y. Yang, H. Chen, J. Am. Chem. Soc. 2012, 134, 1200.

[36] D. Cheng, J. Peng, Y. Lv, D. Su, D. Liu, M. Chen, L. Yuan, X. Zhang, J. Am. Chem. Soc. 2019, 141, 6352.

[37] C. Zhang, H. Xie, T. Zhan, J. Zhang, B. Chen, Z. Qian, G. Zhang, W. Zhang, J. Zhou, Chem. Commun. 2019, 55, 9444.

[38] W. Shi, H. Ma, Chem. Commun. 2012, 48, 8732.

[39] X. Gao, S. Bai, D. Fazzi, T. Niehaus, M. Barbatti, W. Thiel, J. Chem. Theory Comput. 2017, 13, 515.

[40] O. El Bakouri, J. R. Smith, H. Ottosson, J. Am. Chem. Soc. 2020, 142, 5602.

[41] P. White, Ann. N. Y. Acad. Sci. 1970, 174, 23.

[42] A. C. Pena, A. Pamplona, Coord. Chem. Rev. 2022, 453, 214285.

[43] S. W. Ryter, A. M. K. Choi, Transl. Res. 2016, 167, 7.

[44] V. G. Nielsen, E. C. Pearson, M. C. Smith, Artif. Organs 2013, 37, 1008.

[45] T. Li, P. K. Singal, Circulation 2000, 102, 2105.

[46] T. Li, I. Danelisen, A. Belló-Klein, P. K. Singal, Cardiovasc. Res. 2000, 46, 523.

[47] R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, A. Takeshita, Circulation 2002, 106, 362.

[48] E. El-Demerdash, A. S. Awad, R. M. Taha, A. M. El-Hady, M. M. Sayed-Ahmed, Pharmacol. Res. 2005, 51, 311.

[49] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, Williams , F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery Jr., J. E. Peralta, F. Ogliaro, M. J. Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N. Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, D. J. Fox, Gaussian 16, Revision C.01, Gaussian, Inc, Wallin2019.

[50] F. Neese, F. Wennmohs, U. Becker, C. Riplinger, J. Chem. Phys. 2020, 152, 224108.

[51] F. Neese, WIREs Comput. Mol. Sci. 2022, 12, e1606.

[52] F. Neese, WIREs Comput. Mol. Sci. 2018, 8, e1327.

[53] F. Neese, WIREs Comput. Mol. Sci. 2012, 2, 73.

[54] Z. Shuai, Q. Peng, Natl. Sci. Rev. 2017, 4, 224.

[55] Z. Shuai, Chin. J. Chem. 2020, 38, 1223.

[56] Y. Niu, Q. Peng, Z. Shuai, Sci. China, Ser. B:Chem. 2008, 51, 1153.

[57] Q. Peng, Y. Yi, Z. Shuai, J. Shao, J. Am. Chem. Soc. 2007, 129, 9333.

[58] Z. Shuai, Q. Peng, Phys. Rep. 2014, 537, 123.

[59] Y. Niu, W. Li, Q. Peng, H. Geng, Y. Yi, L. Wang, G. Nan, D. Wang, Z. Shuai, Mol. Phys. 2018, 116, 1078.

[60] T. Lu, F. Chen, J. Comput. Chem. 2012, 33, 580.

[61] W. Humphrey, A. Dalke, K. Schulten, J. Mol. Graphics 1996, 14, 33.

Rights & permissions

2026 The Author(s). Smart Molecules published by John Wiley & Sons Australia, Ltd on behalf of Dalian University of Technology.