Abstract
Replicating biological systems using non-living materials, from the foundational molecular level to complex tissue structures, is central to abiotic mimicry. Enzymes play a vital role in these systems; however, replicating their enzymatic power with minimal components remains a key challenge. Here we show that gallium in the liquid state exhibits nuclease-like activity with preferred cleaving sites. The mechanism involves nucleotide-biased adsorption and hydroxyl radical-assisted phosphodiester hydrolysis. Compared with previously reported artificial metallonucleases, the liquid gallium uniquely integrates its oxide layer for substrate adsorption and its metallic core with electrons as a cleavage active center, forming a ligand- and cofactor-free artificial nuclease platform. Moreover, their activity is tunable through synthesis parameters and external stimuli, enabling programmable control with spatial or temporal precision. This work presents a minimalistic yet functional approach to enzyme mimicry, expanding the design space for abiotic enzymatic systems and offering potential opportunities in therapeutic applications, synthetic biology, and biomaterials.
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Data availability
All mass spectrometry data supporting the findings of this study have been deposited in Zenodo (available at: https://doi.org/10.5281/zenodo.19041335)43. All ONT sequencing data have been deposited in the National Center for Biotechnology Information GenBank under BioProject PRJNA1307762. The reference plasmid sequence (pUC19) is available in GenBank under accession number M77789.2 [https://www.ncbi.nlm.nih.gov/nuccore/M77789.2]. Source data are provided in this paper.
Code availability
The scripts used for processing ONT DNA sequencing data are available in Code Ocean (https://doi.org/10.24433/CO.3229876.v3)22.
References
Egan, P., Sinko, R., LeDuc, P. R. & Keten, S. The role of mechanics in biological and bio-inspired systems. Nat. Commun. 6, 7418 (2015).
Leveson-Gower, R. B., Mayer, C. & Roelfes, G. The importance of catalytic promiscuity for enzyme design and evolution. Nat. Rev. Chem. 3, 687–705 (2019).
Cowan, J. A. Chemical nucleases. Curr. Opin. Chem. Biol. 5, 634–642 (2001).
Jiang, Q., Xiao, N., Shi, P., Zhu, Y. & Guo, Z. Design of artificial metallonucleases with oxidative mechanism. Coord. Chem. Rev. 251, 1951–1972 (2007).
Mancin, F., Scrimin, P., Tecilla, P. & Tonellato, U. Artificial metallonucleases. Chem. Commun. 2540–2548 https://doi.org/10.1039/B418164F (2005).
Yu, Z. & Cowan, J. A. Metal complexes promoting catalytic cleavage of nucleic acids—biochemical tools and therapeutics. Curr. Opin. Chem. Biol. 43, 37–42 (2018).
Kameshima, W. et al. Conjugation of peptide nucleic acid with a pyrrole/imidazole polyamide to specifically recognize and cleave DNA. Angew Chem. Int. Ed. Engl. 52, 13681–13684 (2013).
Lu, X. & Zhang, C. Rational design of site-specific artificial metallonucleases for therapeutic applications. Microchem. J. 213, 113736 (2025).
Fu, M. et al. Gallium-based liquid metal micro/nanoparticles for photothermal cancer therapy. J. Mater. Sci. Technol. 142, 22–33 (2023).
Deng, Y. et al. Stretchable liquid metal based biomedical devices. Npj Flex. Electron. 8, 12 (2024).
Gao, W., Wang, Y., Wang, Q., Ma, G. & Liu, J. Liquid metal biomaterials for biomedical imaging. J. Mater. Chem. B 10, 829–842 (2022).
Tang, S.-Y., Tabor, C., Kalantar-Zadeh, K. & Dickey, M. D. Gallium liquid metal: The devil’s elixir. Annu. Rev. Mater. Res. 51, 381–408 (2021).
Xie, W. et al. Gallium-based liquid metal particles for therapeutics. Trends Biotechnol. 39, 624–640 (2021).
Fatima, S. S. et al. Current state and future prospects of liquid metal catalysis. Nat. Catal. 6, 1131–1139 (2023).
Kalantar-Zadeh, K., Daeneke, T. & Tang, J. The atomic intelligence of liquid metals. Science 385, 372–373 (2024).
Rahim, M. A. et al. Low-temperature liquid platinum catalyst. Nat. Chem. 14, 935–941 (2022).
Tang, J. et al. Dynamic configurations of metallic atoms in the liquid state for selective propylene synthesis. Nat. Nanotechnol. 19, 306–310 (2024).
Cao, G. et al. Liquid metal for high-entropy alloy nanoparticles synthesis. Nature 619, 73–77 (2023).
Wang, C., Wang, T., Zeng, M. & Fu, L. Emerging liquid metal catalysts. J. Phys. Chem. Lett. 14, 10054–10066 (2023).
Zhang, C. et al. Gallium nanodroplets are anti-inflammatory without interfering with iron homeostasis. ACS Nano 16, 8891–8903 (2022).
Jiao, L. et al. Nuclease-mimetic nanomaterials: From fundamentals to bioapplications. Small 21, 2502660 (2025).
Liu, L. Code for “Gallium in liquid state shows nuclease-mimicking activity. Code Ocean https://doi.org/10.24433/CO.3229876.v3 (2026).
Creighton, M. A. et al. Oxidation of gallium-based liquid metal alloys by water. Langmuir 36, 12933–12941 (2020).
Liu, T. et al. Photothermal photodynamic therapy and enhanced radiotherapy of targeting copolymer-coated liquid metal nanoparticles on liver cancer. Colloids Surf. B Biointerfaces 207, 112023 (2021).
Pei, S., You, S., Ma, J., Chen, X. & Ren, N. Electron spin resonance evidence for electro-generated hydroxyl radicals. Environ. Sci. Technol. 54, 13333–13343 (2020).
Clément, J.-L. et al. Assignment of the epr spectrum of 5,5-dimethyl-1-pyrroline n-oxide (dmpo) superoxide spin adduct. J. Org. Chem. 70, 1198–1203 (2005).
Villamena, F. A., Merle, J. K., Hadad, C. M. & Zweier, J. L. Superoxide radical anion adduct of 5,5-dimethyl-1-pyrroline n-oxide (dmpo). 1. The thermodynamics of formation and its acidity. J. Phys. Chem. A 109, 6083–6088 (2005).
Diaz-Uribe, C. E. et al. Visible light superoxide radical anion generation by tetra(4-carboxyphenyl)porphyrin/tio2: Epr characterization. J. Photochem. Photobiol. A 215, 172–178 (2010).
Burchill, C. E. & Ginns, I. S. The radiation-induced oxidation of ethanol and methanol by hydrogen peroxide in aqueous solution. Can. J. Chem. 48, 2628–2632 (1970).
Villamena, F. A., Merle, J. K., Hadad, C. M. & Zweier, J. L. Superoxide radical anion adduct of 5,5-dimethyl-1-pyrroline n-oxide (dmpo). 2. The thermodynamics of decay and epr spectral properties. J. Phys. Chem. A 109, 6089–6098 (2005).
Sakamoto, T. & Imai, H. Hydrogen peroxide produced by superoxide dismutase sod-2 activates sperm in caenorhabditis elegans. J. Biol. Chem. 292, 14804–14813 (2017).
Hyland, K. & Auclair, C. The formation of superoxide radical anions by a reaction between o2, oh− and dimethyl sulfoxide. Biochem. Biophys. Res. Commun. 102, 531–537 (1981).
Bansal, S. & Wang, B. A critical factor in reactive oxygen species (ros) studies: The need to understand the chemistry of the solvent used: The case of dmso. Chem. Sci. 15, 17843–17851 (2024).
Goff, A. et al. An exploration into two-dimensional metal oxides, and other 2d materials, synthesised via liquid metal printing and transfer techniques. Dalton Trans. 50, 7513–7526 (2021).
Lu, H. et al. Nanoengineering liquid metal core–shell nanostructures. Adv. Funct. Mater. 34, 2311300 (2024).
Hsieh, T.-E., Frisch, J., Wilks, R. G. & Bär, M. Unravelling the surface oxidation-induced evolution of the electronic structure of gallium. ACS Appl. Mater. Interfaces 15, 47725–47732 (2023).
Ding, Y., Zeng, M. & Fu, L. Surface chemistry of gallium-based liquid metals. Matter 3, 1477–1506 (2020).
Gabovich, A. M., Kuznetsov, V. I. & Voitenko, A. I. Tunneling as a marker of quantum mechanics. Low Temp. Phys. 50, 925–947 (2024).
Lin, Y., Liu, Y., Genzer, J. & Dickey, M. D. Shape-transformable liquid metal nanoparticles in aqueous solution. Chem. Sci. 8, 3832–3837 (2017).
He, J., Shi, F., Wu, J. & Ye, J. Shape transformation mechanism of gallium–indium alloyed liquid metal nanoparticles. Adv. Mater. Interf. 8, 2001874 (2021).
Ye, S. et al. Oxidation-induced oxide shell rupture and phase separation in eutectic gallium–indium nanoparticles. ACS Nano 18, 25107–25117 (2024).
Chiu, S.-H. et al. Electrochromic pedot:Pss with embedded liquid gallium nanoparticles. ACS Appl. Mater. Interfaces 17, 43968–43978 (2025).
Liu, L., Zheng, J., Lu, X., Kalantar-Zadeh, K. & Zhang, C. Mass spectrometry data for “gallium in liquid state shows nuclease-mimicking activity”. Zenodo https://doi.org/10.5281/zenodo.19041335 (2026).
Chattopadhyaya, R. Oxidative damage to DNA constituents by iron-mediated fenton reactions-the thymidine family. J. Biomol. Struct. Dyn. 32, 155–169 (2014).
Burrows, C. J. & Muller, J. G. Oxidative nucleobase modifications leading to strand scission. Chem. Rev. 98, 1109–1152 (1998).
Sträter, N., Lipscomb, W. N., Klabunde, T. & Krebs, B. Two-metal ion catalysis in enzymatic acyl- and phosphoryl-transfer reactions. Angew. Chem. Int. Ed. 35, 2024–2055 (1996).
Weston, J. Mode of action of bi- and trinuclear zinc hydrolases and their synthetic analogues. Chem. Rev. 105, 2151–2174 (2005).
Tang, J. et al. Liquid-metal-enabled mechanical-energy-induced co2 conversion. Adv. Mater. 34, 2105789 (2022).
Mahmoudi, M., Landry, M. P., Moore, A. & Coreas, R. The protein corona from nanomedicine to environmental science. Nat. Rev. Mater. 8, 422–438 (2023).
Liu, L. et al. Composites from self-assembled protein nanofibrils and liquid metal gallium. Adv. Funct. Mater. 34, 2405918 (2024).
Weston, S. A., Lahm, A. & Suck, D. X-ray structure of the dnase i-d(ggtatacc)2 complex at 2·3å resolution. J. Mol. Biol. 226, 1237–1256 (1992).
Ni, J., Pomerantz, C., Rozenski, J., Zhang, Y. & McCloskey, J. A. Interpretation of oligonucleotide mass spectra for determination of sequence using electrospray ionization and tandem mass spectrometry. Anal. Chem. 68, 1989–1999 (1996).
Potier, N., Van Dorsselaer, A., Cordier, Y., Roch, O. & Bischoff, R. Negative electrospray ionization mass spectrometry of synthetic and chemically modified oligonucleotides. Nucleic Acids Res. 22, 3895–3903 (1994).
Acknowledgements
K.K.-Z. acknowledges support from the Australian Research Council (ARC) Discovery Project (DP240101086). C.Z. acknowledges support from the Engineering and Physical Sciences Research Council (EPSRC New Investigator Award, APP34994), Royal Society (Grant Nos. RG/R1/241228, IEC/NSFC/233339 and IES/R2/252009), UK. M.J.S.S. acknowledges support from the ARC Discovery Project (DP240101215). This research was supported by the Australian Government’s National Collaborative Research Infrastructure Strategy (NCRIS), with computational resources provided by the National Computational Infrastructure (NCI) Facility and the Pawsey Supercomputing Research Center through the National Computational Merit Allocation Scheme. We acknowledge Professor Ewa Magdalena Goldys for providing experimental resources. Technical assistance from Dr. Lewis Adler at the Bioanalytical Mass Spectrometry Facility (Mark Wainwright Analytical Center, UNSW Sydney) is gratefully acknowledged. We acknowledge the facilities provided by Sydney Analytical and the technical support of Dr. Hongwei Liu at Sydney Microscopy and Microanalysis. The assistance of high-performance computing resources from the UNSW Katana server is also acknowledged. We thank Matthew Wong, Lydia Murphy, and Aravind Manda at the Ramaciotti Center for Genomics for their technical assistance with Oxford Nanopore Technology. We also thank Yujian Shi from the Dr. Sarina Sarina’s group and Dr. Daniele Vigolo for providing essential chemicals for the experiment and access to equipment.
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The conceptual framework for this work was developed by C.Z. and K.K.-Z. Initial experiments and preliminary data were generated by C.Z., with help from F.D.; L.L. performed the remaining experiments, with support from C.Z., J.Z., and X.L. on experimental methods design, DFT calculations, mass spectrometry analysis, and mechanistic discussions. The ONT data analysis was performed by L.L. and supervised by M.A.S. B.M. performed the EPR simulations and assisted with EPR analysis. The following individuals contributed expertise and provided theoretical or experimental resources or valuable suggestions: C.S., Y.W., X.W., F.D., N.-A.N.-A., F.Z., S.-H.C., M.T., Y.L., S.-Y.T., J.T., M.J.S.S., and P.V.K. The first manuscript was drafted by L.L. with input from C.Z., J.Z., X.L., and K.K.-Z. All authors discussed the results and contributed to the preparation of the final version of the paper.
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Liu, L., Zheng, J., Lu, X. et al. Gallium in liquid state shows nuclease-mimicking activity. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71346-7
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DOI: https://doi.org/10.1038/s41467-026-71346-7
