Abstract
The development of micro- and nanorobots has amplified the demand for intelligent multifunctional machines in biomedical applications, but most microrobotic systems struggle to achieve the attributes needed for those applications. Here we introduce enzymatic microbubble robots that exhibit steerable motion, enhanced biodegradability, high in vivo imaging contrast, and effective targeting and penetration of disease sites. These microrobots feature natural protein shells modified with urease to decompose bioavailable urea for autonomous propulsion, whereas an internal microbubble serves as an ultrasound imaging contrast agent for deep tissue imaging and navigation. Magnetic nanoparticle integration enables imaging-guided magnetically controlled motion and catalase functionalization facilitates chemotactic movement towards hydrogen peroxide gradients, directing robots to tumour sites. Focused ultrasound triggers robot shell collapse and inertial cavitation of the released microbubbles, creating mechanical forces that enhance therapeutic payload penetration. In vivo studies validate the tumour-targeting and therapeutic efficacy of these robots, demonstrating enhanced antitumour effects. This multifunctional microbubble robotic platform has the potential to transform medical interventions and precision therapies.
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Data availability
The data supporting the results in this study are available within the paper and its Supplementary Information. Source data are provided with this paper.
Code availability
The custom MATLAB code for the Keller–Miksis dynamic model simulations in this study is available via Zenodo at https://doi.org/10.5281/zenodo.17717384 (ref. 65).
References
Nelson, B. J. & Pané, S. Delivering drugs with microrobots. Science 382, 1120–1122 (2023).
Almeida, H., Traverso, G., Sarmento, B. & das Neves, J. Nanoscale anisotropy for biomedical applications. Nat. Rev. Bioeng. 2, 609–625 (2024).
Kim, K., Guo, J., Liang, Z. & Fan, D. Artificial micro/nanomachines for bioapplications: biochemical delivery and diagnostic sensing. Adv. Funct. Mater. 28, 1705867 (2018).
Li, J., de Ávila, B. E.-F., Gao, W., Zhang, L. & Wang, J. Micro/nanorobots for biomedicine: delivery, surgery, sensing, and detoxification. Sci. Robot. 2, eaam6431 (2017).
Elnaggar, A., Kang, S., Tian, M., Han, B. & Keshavarz, M. State of the art in actuation of micro/nanorobots for biomedical applications. Small Sci. 4, 2300211 (2024).
Simo, C. et al. Urease-powered nanobots for radionuclide bladder cancer therapy. Nat. Nanotechnol. 19, 554–564 (2024).
Zhang, H. et al. Dual-responsive biohybrid neutrobots for active target delivery. Sci. Robot. 6, 9519eaaz (2021).
Yoo, J., Tang, S. & Gao, W. Micro- and nanorobots for biomedical applications in the brain. Nat. Rev. Bioeng. 1, 308–310 (2023).
Wu, Z. et al. A swarm of slippery micropropellers penetrates the vitreous body of the eye. Sci. Adv. 4, eaat4388 (2018).
Wang, Y. et al. Microrobots for targeted delivery and therapy in digestive system. ACS Nano 17, 27–50 (2023).
Wu, Z. et al. Oral mitochondrial transplantation using nanomotors to treat ischaemic heart disease. Nat. Nanotechnol. 19, 1375–1385 (2024).
Yan, M. et al. Site-selective superassembly of biomimetic nanorobots enabling deep penetration into tumor with stiff stroma. Nat. Commun. 14, 4628 (2023).
Wu, X. et al. Self-adaptive magnetic liquid metal microrobots capable of crossing biological barriers and wireless neuromodulation. ACS Nano 18, 29558–29571 (2024).
Law, J. et al. Microrobotic swarms for selective embolization. Sci. Adv. 8, eabm5752 (2022).
Go, G. et al. Multifunctional microrobot with real-time visualization and magnetic resonance imaging for chemoembolization therapy of liver cancer. Sci. Adv. 8, eabq8545 (2022).
Del Campo Fonseca, A. et al. Ultrasound trapping and navigation of microrobots in the mouse brain vasculature. Nat. Commun. 14, 5889 (2023).
Kim, J. et al. Advanced materials for micro/nanorobotics. Chem. Soc. Rev. 53, 9190–9253 (2024).
Peng, F., Tu, Y. & Wilson, D. A. Micro/nanomotors towards in vivo application: cell, tissue and biofluid. Chem. Soc. Rev. 46, 5289–5310 (2017).
Yong, J., Mellick, A. S., Whitelock, J., Wang, J. & Liang, K. A biomolecular toolbox for precision nanomotors. Adv. Mater. 35, e2205746 (2023).
Huang, T.-Y., Gu, H. & Nelson, B. J. Increasingly intelligent micromachines. Annu. Rev. Control Robot. Auton. Syst. 5, 279–310 (2022).
Law, J. et al. Micro/nanorobotic swarms: from fundamentals to functionalities. ACS Nano 17, 12971–12999 (2023).
Mujtaba, J. et al. Micro-bio-chemo-mechanical-systems: micromotors, microfluidics, and nanozymes for biomedical applications. Adv. Mater. 33, e2007465 (2021).
Cao, S. et al. Photoactivated nanomotors via aggregation induced emission for enhanced phototherapy. Nat. Commun. 12, 2077 (2021).
Zhao, H. et al. Intelligent metallic micro/nanomotors: from propulsion to application. Nano Today 52, 101939 (2023).
Tang, S. et al. Enzyme-powered janus platelet cell robots for active and targeted drug delivery. Sci. Robot. 5, eaba6137 (2020).
Medina-Sanchez, M., Schwarz, L., Meyer, A. K., Hebenstreit, F. & Schmidt, O. G. Cellular cargo delivery: toward assisted fertilization by sperm-carrying micromotors. Nano Lett. 16, 555–561 (2016).
Go, G. et al. Human adipose–derived mesenchymal stem cell–based medical microrobot system for knee cartilage regeneration in vivo. Sci. Robot. 5, eaay6626 (2020).
Felfoul, O. et al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nat. Nanotechnol. 11, 941–947 (2016).
Alapan, Y. et al. Soft erythrocyte-based bacterial microswimmers for cargo delivery. Sci. Robot. 3, eaar4423 (2018).
Zhang, F. et al. Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia. Nat. Mater. 21, 1324–1332 (2022).
Yan, X. et al. Multifunctional biohybrid magnetite microrobots for imaging-guided therapy. Sci. Robot. 2, eaaq1155 (2017).
Ceylan, H. et al. 3D printed personalized magnetic micromachines from patient blood–derived biomaterials. Sci. Adv. 7, eabh0273 (2021).
Tang, S. et al. Bacterial outer membrane vesicle nanorobot. Proc. Natl Acad. Sci. USA 121, e2403460121 (2024).
Zhang, F. et al. Biomembrane-functionalized micromotors: biocompatible active devices for diverse biomedical applications. Adv. Mater. 34, e2107177 (2022).
Huang, G. et al. Cell-based intelligent micro/nanorobots for precise regulation and active biotherapy. Matter 6, 4158–4194 (2023).
Wang, B., Kostarelos, K., Nelson, B. J. & Zhang, L. Trends in micro-/nanorobotics: materials development, actuation, localization, and system integration for biomedical applications. Adv. Mater. 33, 2002047 (2020).
Gao, C. et al. Biomedical micro-/nanomotors: from overcoming biological barriers to in vivo imaging. Adv. Mater. 33, 2000512 (2020).
Singh, A. K., Awasthi, R. & Malviya, R. Bioinspired microrobots: opportunities and challenges in targeted cancer therapy. J. Control. Release 354, 439–452 (2023).
Wan, M., Li, T., Chen, H., Mao, C. & Shen, J. Biosafety, functionalities, and applications of biomedical micro/nanomotors. Angew. Chem. Int. Ed. 60, 13158–13176 (2021).
Hortelao, A. C. et al. Swarming behavior and in vivo monitoring of enzymatic nanomotors within the bladder. Sci. Robot. 6, eabd2823 (2021).
Zhang, B. et al. Twin-bioengine self-adaptive micro/nanorobots using enzyme actuation and macrophage relay for gastrointestinal inflammation therapy. Sci. Adv. 9, eadc8978 (2023).
Dasgupta, A. et al. Nonspherical ultrasound microbubbles. Proc. Natl Acad. Sci. USA 120, e2218847120 (2023).
Xu, F., Wang, W.-H., Tan, Y.-J. & Bruening, M. L. Facile trypsin immobilization in polymeric membranes for rapid, efficient protein digestion. Anal. Chem. 82, 10045–10051 (2010).
Ma, X., Wang, X., Hahn, K. & Sanchez, S. Motion control of urea-powered biocompatible hollow microcapsules. ACS Nano 10, 3597–3605 (2016).
Wang, W., Duan, W., Ahmed, S., Mallouk, T. E. & Sen, A. Small power: autonomous nano- and micromotors propelled by self-generated gradients. Nano Today 8, 531–554 (2013).
Mulvana, H., Eckersley, R. J., Tang, M.-X., Pankhurst, Q. & Stride, E. Theoretical and experimental characterisation of magnetic microbubbles. Ultrasound Med. Biol. 38, 864–875 (2012).
Crake, C. et al. Enhancement and passive acoustic mapping of cavitation from fluorescently tagged magnetic resonance-visible magnetic microbubbles in vivo. Ultrasound Med. Biol. 42, 3022–3036 (2016).
Chertok, B. & Langer, R. Circulating magnetic microbubbles for localized real-time control of drug delivery by ultrasonography-guided magnetic targeting and ultrasound. Theranostics 8, 341 (2018).
Beguin, E. et al. Magnetic microbubble mediated chemo-sonodynamic therapy using a combined magnetic-acoustic device. J. Control. Release 317, 23–33 (2020).
Gusliakova, O. I. et al. Magnetically navigated microbubbles coated with albumin/polyarginine and superparamagnetic iron oxide nanoparticles. Biomater. Adv. 158, 213759 (2024).
Owen, J. et al. Magnetic targeting of microbubbles against physiologically relevant flow conditions. Interface Focus 5, 20150001 (2015).
Lee, H. et al. Microbubbles used for contrast enhanced ultrasound and theragnosis: a review of principles to applications. Biomed. Eng. Lett. 7, 59–69 (2017).
Maas, M., Todenhöfer, T. & Black, P. C. Urine biomarkers in bladder cancer—current status and future perspectives. Nat. Rev. Urol. 20, 597–614 (2023).
Kaufman, D. S., Shipley, W. U. & Feldman, A. S. Bladder cancer. Lancet 374, 239–249 (2009).
Douglass, L. & Schoenberg, M. The future of intravesical drug delivery for non-muscle invasive bladder cancer. Bladder Cancer 2, 285–292 (2016).
Somasundar, A. et al. Positive and negative chemotaxis of enzyme-coated liposome motors. Nat. Nanotechnol. 14, 1129–1134 (2019).
Keenan, T. M. & Folch, A. Biomolecular gradients in cell culture systems. Lab Chip 8, 34–57 (2008).
Ralph, S. J. & Reynolds, M. J. Intratumoral pro-oxidants promote cancer immunotherapy by recruiting and reprogramming neutrophils to eliminate tumors. Cancer Immunol. Immunother. 72, 527–542 (2023).
Szatrowski, T. P. & Nathan, C. F. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794–798 (1991).
Bar-Zion, A. et al. Acoustically triggered mechanotherapy using genetically encoded gas vesicles. Nat. Nanotechnol. 16, 1403–1412 (2021).
Xiu, W. et al. Ultrasound-responsive catalytic microbubbles enhance biofilm elimination and immune activation to treat chronic lung infections. Sci. Adv. 9, eade5446 (2023).
Chen, S. et al. A review of bioeffects induced by focused ultrasound combined with microbubbles on the neurovascular unit. J. Cereb. Blood Flow Metab. 42, 3–26 (2022).
Şen, T., Tüfekçioğlu, O. & Koza, Y. Mechanical index. Anat. J. Cardiol. 15, 334 (2015).
Lakshmanan, A. et al. Preparation of biogenic gas vesicle nanostructures for use as contrast agents for ultrasound and MRI. Nat. Protoc. 12, 2050–2080 (2017).
Criado-Hidalgo, E. Keller-Miksis dynamic model simulations of CBRs. Zenodo https://doi.org/10.5281/zenodo.17717384 (2025).
Acknowledgements
This work was supported by the National Science Foundation grant (number 1931214, to W.G.) and the Heritage Medical Research Institute. We acknowledge D. M. Silevitch and P. J. Gunnarson from Caltech for support in assessing the magnetic properties and PIV analysis of bubble robots, respectively. We thank H. Salinas and C. Zavaleta from the University of Southern California (USC) for supporting the animal tests.
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Contributions
S.T. and W.G. conceived the project. S.T. led the microrobot development. H.H., X.M., P.N.P., C.G., J.Z., E.C.-H., J.Y., J.L., G.K., S.Y. and D.W. contributed to the preparation and characterization of the microrobots. W.G., M.G.S. and Q.Z. supervised the work. S.T. and W.G. co-wrote the paper. All authors contributed to the data analysis and provided feedback on the manuscript.
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Nature Nanotechnology thanks Daniel Ahmed and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary information
Supplementary Information
Supplementary Notes 1–3 and Figs. 1–34.
Supplementary Video 1
Propulsion of MBRs in urea solutions without or with magnetic control.
Supplementary Video 2
Motion of bare bubbles in urea solutions.
Supplementary Video 3
Propulsion of MBRs and bubble-MNP in biological fluids without or with magnetic control.
Supplementary Video 4
Propulsion of MBRs in urea solutions after storage.
Supplementary Video 5
US imaging of MBR motion within a microfluidic chamber.
Supplementary Video 6
US imaging of magnetically guided MBR motion within a microfluidic chamber.
Supplementary Video 7
US imaging of magnetically guided MBR motion across a narrow microchannel.
Supplementary Video 8
US imaging of MBR motion within a mouse bladder.
Supplementary Video 9
US imaging of magnetically guided MBR motion within a mouse bladder.
Supplementary Video 10
Propulsion of CBRs in urea solutions.
Supplementary Video 11
Propulsion of CBRs in biological fluids.
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Source data for Fig. 4.
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Tang, S., Han, H., Ma, X. et al. Enzymatic microbubble robots. Nat. Nanotechnol. (2026). https://doi.org/10.1038/s41565-025-02109-6
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DOI: https://doi.org/10.1038/s41565-025-02109-6
