Fuel-propelled nanomotors for acute kidney injury applications

Abstract

Acute kidney injury (AKI) is characterized by a rapid loss of renal metabolic function and a high mortality rate. Although significant progress has been made in developing targeted drugs for AKI treatment, issues such as inadequate antioxidant effects and poor renal enrichment efficiency remain. Nanomotors can enhance drug delivery efficiency in AKI treatments through self-propulsion in the microenvironment or via external stimuli. We reviewed recent progress in the targeted treatment of AKI with nanomotors, focusing on their contribution to targeted drug delivery at different stages and combined treatments. Current limitations and future development directions are also discussed.

Keywords

Acute kidney injury / Renal enrichment efficiency / Nanomotors / Drug delivery / Self-propulsion

Funding information

This study was supported by the Shandong Provincial Natural Science Fund (Grant No. ZR2022ME168), and Binzhou Medical University Scientific Research Launch Fund Project (Grant No. BY2019KYQD29), and Binzhou Medical University Science and Technology Plan Project (Grant No. BY2020KJ28).

Conflicts of interest

The authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this article.

Data availability

Not applicable.

Ethics approval

Not applicable.

CRediT authorship contribution statement

Weixin Wang: Writing - original draft. Rui Gao: Investigation. Lin Zhang: Investigation. Zhongchao Wang: Formal analysis. Jiahui Sun: Methodology. Lei Luo: Software, Resources. Min Pan: Investigation. Miaofang Hong: Investigation. Jianming Wu: Resources, Investigation. Qibing Mei: Software, Resources, Methodology, Investigation. Ke Tong: Software, Resources. Yini Wang: Writing - review & editing, Resources. Lingyan Qiao: Writing - review & editing, Investigation. Fei Tong: Writing - review & editing.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fei Tong reports financial support was provided by Binzhou Medical University. Fei Tong reports a relationship with Binzhou Medical University that includes: employment. Fei Tong has patent no pending to no. no If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

Not applicable.

References

[1] J. Kellum, P. Romagnani, G. Ashuntantang, C. Ronco, A. Zarbock, H. Anders, Acute kidney injury, Nat. Rev. Dis. Prim. 7 (2021) 52. https://doi.org/10.1038/s41572-021-00284-z.

[2] H. Wang, D. Yu, J. Fang, Y. Zhou, D. Li, Z. Liu, J. Ren, X. Qu, Phenol-like group functionalized graphene quantum dots structurally mimicking natural antioxidants for highly efficient acute kidney injury treatment, Chem. Sci. 11 (2020) 12721-12730. https://doi.org/10.1039/D0SC03246H.

[3] T. Vukićević, C. Hinze, S. Baltzer, N. Himmerkus, C. Quintanova, K. Zühlke, F. Compton, R. Ahlborn, A. Dema, J. Eichhorst, B. Wiesner, M. Bleich, K.M. Schmidt-Ott, E. Klussmann, Fluconazole increases osmotic water transport in renal collecting duct through effects on aquaporin-2 trafficking, J. Am. Soc. Nephrol. 30 (2019) 795-810. https://doi.org/10.1681/ASN.2018060668.

[4] R. Lin, W. Yu, X. Chen, H. Gao, Self-propelled micro/nanomotors for tumor targeting delivery and therapy, Adv. Healthcare Mater. 10 (2021) e2001212. https://doi.org/10.1002/adhm.202001212.

[5] M.J. Mitchell, M.M. Billingsley, R.M. Haley, M.E. Wechsler, N.A. Peppas, R. Langer, Engineering precision nanoparticles for drug delivery, Nature. Reviews. Drug, Discovery 20 (2021) 101-124. https://doi.org/10.1038/s41573-020-0090-8.

[6] C. Timchalk, D.R. Finco, J.F. Quast, Evaluation of renal function in rhesus monkeys and comparison to beagle dogs following oral administration of the organic acid triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid), Fund. Appl. Toxicol. 36 (1997) 47-53. https://doi.org/10.1093/toxsci/36.1.47.

[7] D. Liu, G. Shu, F. Jin, J. Qi, X. Xu, Y. Du, H. Yu, J. Wang, M. Sun, Y. You, M. Zhu, M. Chen, L. Zhu, Q. Shen, X. Ying, X. Lou, S. Jiang, Y. Du, ROS-responsive chitosan-SS31 prodrug for AKI therapy via rapid distribution in the kidney and long-term retention in the renal tubule, Sci. Adv. 6 (2020) eabb7422. https://doi. org/10.1126/sciadv.abb7422.

[8] H. Li, F. Peng, X. Yan, C. Mao, X. Ma, D.A. Wilson, Q. He, Y. Tu, Medical microand nanomotors in the body, Acta Pharm. Sin. B 13 (2023) 517-541. https://doi.org/10.1016/j.apsb.2022.10.010.

[9] Z. Liang, Y. Tu, F. Peng, Polymeric micro/nanomotors and their biomedical applications, Adv. Healthcare Mater. 10 (2021) e2100720. https://doi.org/10.1002/adhm.202100720.

[10] H. Zhang, Z. Li, C. Gao, X. Fan, Y. Pang, T. Li, Z. Wu, H. Xie, Q. He, Dualresponsive biohybrid neutrobots for active target delivery, Sci. Robot. 6 (2021) eaaz9519. https://doi.org/10.1126/scirobotics.aaz9519.

[11] T. Lee, M. Alarcón-Correa, C. Miksch, K. Hahn, J. G Gibbs, P. Fischer, Selfpropelling nanomotors in the presence of strong Brownian forces, Nano Lett. 14 (2014) 2407-2412. https://doi.org/10.1021/nl500068n.

[12] L. Wang, M. Marciello, M. Estévez-Gay, P.E.D. Soto Rodriguez, Y. Luengo Morato, J. Iglesias-Fernández, X. Huang, S. Osuna, M. Filice, S. Sánchez, Enzyme conformation influences the performance of lipase-powered nanomotors, Angew. Chem. Int. Ed. Engl. 59 (2020) 21080-21087. https://doi.org/10.1002/ange.202008339.

[13] L. Wang, A.C. Hortel-ao, X. Huang, S. Sánchez, Lipase-powered mesoporous silica nanomotors for triglyceride degradation, Angew. Chem. Int. Ed. 58 (2019) 7992-7996. https://doi.org/10.1002/anie.201900697.

[14] Y. Yang, L. Wang, X. Huang, MOF-based micro/nanomotors (MOFtors): recent progress and challenges, Coordination, Chem. Rev. 495 (2023) 215372. https://doi.org/10.1016/j.ccr.2023.215372.

[15] L. Wang, Y. Huang, H. Xu, S. Chen, H. Chen, Y. Lin, X. Wang, X. Liu, S. Sánchez, X. Huang, Contaminats-fueled laccase-powered Fe3O4@SiO2 nanomotors for synergistical degradation of multiple pollutants, Mater. Today Chem. 26 (2022) 101059. https://doi.org/10.1016/j.mtchem.2022.101059.

[16] L. Wang, K. Villa, Self-propelled micro/nanomotors for removal of insoluble water contaminants: microplastics and oil spills, Environ. Sci.: Nano 8 (2021) 3440. https://doi.org/10.1039/D1EN00663K.

[17] W. Gao, S. Sattayasamitsathit, J. Orozco, J. Wang, Highly efficient catalytic microengines: template electrosynthesis of polyaniline/platinum microtubes, J. Am. Chem. Soc. 133 (2011) 11862-11864. https://doi.org/10.1039/D1EN00663K.

[18] W. Gao, S. Sattayasamitsathit, K.M. Manesh, D. Weihs, J. Wang, Magnetically powered flexible metal nanowire motors, J. Am. Chem. Soc. 132 (2010) 14403-14405. https://doi.org/10.1021/ja1072349.

[19] X. Ma, A. Jannasch, U.R. Albrecht, K. Hahn, A. Miguel-López, E. Schäffer, S. Sánchez, Enzyme-powered hollow mesoporous janus nanomotors, Nano Lett. 15 (2015) 7043-7050. https://doi.org/10.1021/acs.nanolett.5b03100.

[20] L. Zhang, J.J. Abbott, L. Dong, K.E. Peyer, B.E. Kratochvil, H. Zhang, C. Bergeles, B.J. Nelson, Characterizing the swimming properties of artificial bacterial flagella, Nano Lett. 9 (2009) 3663-3667. https://doi.org/10.1021/nl901869j.

[21] B. Sezen, D. Sames, Oxidative C-arylation of free (NH)-heterocycles via direct sp3 C-H bond functionalization, J. Am. Chem. Soc. 126 (2004) 13244-13246. https://doi.org/10.1021/ja045402b.

[22] D.A. Wilson, R.J. Nolte, J.C. van Hest, Autonomous movement of platinum-loaded stomatocytes, Nat. Chem. 4 (2012) 268-274. https://doi.org/10.1038/nchem.1281.

[23] M. Wan, Q. Wang, X. Li, B. Xu, D. Fang, T. Li, Y. Yu, L. Fang, Y. Wang, M. Wang, F. Wang, C. Mao, J. Shen, J. Wei, Systematic research and evaluation models of nanomotors for cancer combined therapy, Angew. Chem. Int. Ed. Engl. 59 (2020) 14458-14465. https://doi.org/10.1002/anie.202002452.

[24] X. Yan, Q. Zhou, M. Vincent, Y. Deng, J. Yu, J. Xu, T. Xu, T. Tang, L. Bian, Y. Wang, K. Kostarelos, L. Zhang, Multifunctional biohybrid magnetite microrobots for imaging-guided therapy, Sci. Robot. 2 (2017) eaaq1155, https://doi.org/10.1126/scirobotics.aaq1155.

[25] C. Gao, Y. Wang, Z. Ye, Z. Lin, X. Ma, Q. He, Biomedical micro-/nanomotors: from overcoming biological barriers to in vivo imaging, Adv. Mater. 33 (2021) e2000512. https://doi.org/10.1002/adma.202000512.

[26] Y. Cao, S. Liu, Y. Ma, L. Ma, M. Zu, J. Sun, F. Dai, L. Duan, B. Xiao, Oral nanomotor-enabled mucus traverse and tumor penetration for targeted chemosono- immunotherapy against colon cancer, Small 18 (2022) e2203466. https://doi.org/10.1002/smll.202203466.

[27] C. Xu, Y. Jiang, H. Wang, Y. Zhang, Y. Ye, H. Qin, J. Gao, Q. Dan, L. Du, L. Liu, F. Peng, Y. Li, Y. Tu, Arthritic microenvironment actuated nanomotors for active rheumatoid arthritis therapy, Adv. Sci. 10 (2023) e2204881. https://doi.org/10.1002/advs.202204881.

[28] N. Zhang, M. Fan, Y. Zhao, X. Hu, Q. Zhu, X. Jiao, Q. Lv, D. Li, Z. Huang, G. Fu, J. Ge, H. Li, W. Zhang, Biomimetic and NOS-responsive nanomotor deeply delivery a combination of MSC-EV and mitochondrial ROS scavenger and promote heart repair and regeneration, Adv. Sci. 10 (2023) e2301440. https://doi.org/10.1002/advs.202301440.

[29] Y. Wu, Z. Song, G. Deng, K. Jiang, H. Wang, X. Zhang, H. Han, Gastric acid powered nanomotors release antibiotics for in vivo treatment of helicobacter pylori infection, Small 17 (2021) e2006877. https://doi.org/10.1002/smll.202006877.

[30] H.E. Yue, X.C. Chang, J.M. Liu, D.K. Zhou, L.Q. Li, Wheel-like magnetic-driven microswarm with a band-aid imitation for patching up microscale intestinal perforation, ACS Appl. Mater. Interfaces 14 (2022) 8743-8752. https://doi.org/10.1021/acsami.1c21352.

[31] Z. Zhao, L. Chen, C. Yang, W. Guo, Y. Huang, W. Wang, M. Wan, C. Mao, J. Shen, Nanomotor-based H(2) S donor with mitochondrial targeting function for treatment of Parkinson’s disease, Bioact. Mater. 31 (2023) 578-589. https://doi.org/10.1016/j.bioactmat.2023.09.001.

[32] M. Tang, J. Ni, Z. Yue, T. Sun, C. Chen, X. Ma, L. Wang, Polyoxometalatenanozyme- Integrated nanomotors (POMotors) for self-propulsion-promoted synergistic photothermal-catalytic tumor therapy, Angew. Chem. Int. Ed. Engl. 63 (2024) e202315031. https://doi.org/10.1002/ange.202315031.

[33] M. Luo, Y. Feng, T. Wang, J. Guan, Micro-/nanorobots at work in active drug delivery, Adv. Funct. Mater. (2018) 1706100. https://doi.org/10.1002/adfm.201706100.

[34] W. Gao, B.E. de ávila, L. Zhang, J. Wang, Targeting and isolation of cancer cells using micro/nanomotors, Adv. Drug Deliv. Rev. 125 (2018) 94-101. https://doi.org/10.1016/j.addr.2017.09.002.

[35] S. Sánchez, L. Soler, J. Katuri, Chemically powered micro- and nanomotors, Angew. Chem. Int. Ed. Engl. 54 (2015) 1414-1444. https://doi.org/10.1002/anie.201406096.

[36] L. Abdelmohsen, F. Peng, Y. Tu, D. A Wilson, Micro-and nano-motors for biomedical applications, J. Mater. Chem. B 2 (2014) 2395-2408. https://doi.org/10.1039/C3TB21451F.

[37] W. Wang, L. Angelica Castro, M. Hoyos, T. E Mallouk, Autonomous motion of metallic microrods propelled by ultrasound, ACS Nano 6 (2012) 6122-6132. https://doi.org/10.1021/nn301312z.

[38] R. Dong, Q. Zhang, W. Gao, A. Pei, B. Ren, Highly efficient light-driven TiO2-Au janus micromotors, ACS Nano 10 (2016) 839-844. https://doi.org/10.1021/acsnano.5b05940.

[39] Y. Gao, F. Wei, Y. Chao, L. Yao, Bioinspired soft microrobots actuated by magnetic field, Biomed. Microdevices 23 (2021) 52. https://doi.org/10.1007/s10544-021-00590-z.

[40] F. Tong, J. Liu, Y. Zhong, Y. Xue, L. Luo, Z. Wang, L. Qiao, X. Zhou, W. Wang, J. Sun, M. Hong, J. Wu, Q. Mei, G. Wu, Carbon monoxide-propelled nanomotors as an active treatment for renal injury, Appl. Mater. Today 32 (2023) 101823. https://doi.org/10.1016/j.apmt.2023.101823.

[41] Q. Yang, L. Xu, W. Zhong, Q. Yan, Y. Gao, W. Hong, Y. She, G. Yang, Recent advances in motion control of micro/nanomotors, Adv. Funct. Mater. 8 (2020) 2000049. https://doi.org/10.1002/aisy.202000049.

[42] H.N. Geo, D.D. Murugan, Z. Chik, A. Norazit, Y.Y. Foo, B.F. Leo, Y.Y. Teo, S.Z. S.B.S.A. Kadir, Y. Chan, H.J. Chai, M. Medel, N.A. Abdullah, E.J. Johns, M.J. Vicent, L.Y. Chung, L.V. Kiew, Renal Nano-drug delivery for acute kidney injury: current status and future perspectives, J. Contr. Release 343 (2022) 237-254. https://doi.org/10.1016/j.jconrel.2022.01.033.

[43] Y. Lin, Y. Li, X. Wang, T. Gong, L. Zhang, X. Sun, Targeted drug delivery to renal proximal tubule epithelial cells mediated by 2-glucosamine, J. Contr. Release 167 (2013) 148-156. https://doi.org/10.1016/j.jconrel.2013.02.001.

[44] S. A Asgeirsdóttir, A.M. A, J. Kamps, H. I Bakker, P. J. Zwiers, P. Heeringa, K. van der Weide, H. van Goor, A. H Petersen, H. Morselt, H. E Moorlag, E. Steenbergen, C. G. Kallenberg, G. Molema, Site-specific inhibition of glomerulonephritis progression by targeted delivery of dexamethasone to glomerular endothelium, Mol. Pharmacol. 72 (2007) 121-131. https://doi.org/10.1124/mol.107.034140.

[45] X. He, Z. Yuan, X. Wu, C. Xu, W. Li, Low molecular weight hydroxyethyl chitosanprednisolone conjugate for renal targeting therapy: synthesis, characterization and in vivo studies, Theranostics 2 (2012) 1054-1063. https://doi.org/10.7150/thno.3705.

[46] Q. Chen, Y. Nan, Y. Yang, Z. Xiao, M. Liu, J. Huang, Y. Xiang, X. Long, T. Zhao, X. Wang, Q. Huang, K. Ai, Nanodrugs alleviate acute kidney injury: manipulate RONS at kidney, Bioact. Mater. 22 (2022) 141-167. https://doi.org/10.1016/j.bioactmat.2022.09.021.

[47] H. Yu, F. Jin, D. Liu, G. Shu, X. Wang, J. Qi, M. Sun, P. Yang, S. Jiang, X. Ying, Y. Du, ROS-responsive nano-drug delivery system combining mitochondriatargeting ceria nanoparticles with atorvastatin for acute kidney injury, Theranostics 10 (2020) 2342-2357. https://doi.org/10.7150/thno.4039.

[48] Q. Huang, Y. Yang, T. Zhao, Q. Chen, M. Liu, S. Ji, Y. Zhu, Y. Yang, J. Zhang, H. Zhao, Y. Nan, K. Ai, Passively-targeted mitochondrial tungsten-based nanodots for efficient acute kidney injury treatment, Bioact. Mater. 21 (2022) 381-393. https://doi.org/10.1016/j.bioactmat.2022.08.022.

[49] Y. Wang, H. Jiang, L. Zhang, P. Yao, S. Wang, Q. Yang, Nanosystems for oxidative stress regulation in the anti-inflammatory therapy of acute kidney injury, Front. Bioeng. Biotechnol. 11 (2023) 1120148. https://doi.org/10.3389/fbioe.2023.1120148.

[50] T. Lan, H. Guo, X. Lu, K. Geng, L. Wu, Y. Luo, J. Zhu, X. Shen, Q. Guo, S. Wu, Dualresponsive curcumin-loaded nanoparticles for the treatment of cisplatin-induced acute kidney injury, Biomacromolecules 23 (2022) 5253-5266. https://doi.org/10.1021/acs.biomac.2c01083.

[51] Z. Li, X. Fan, J. Fan, W. Zhang, J. Liu, B. Liu, H. Zhang, Delivering drugs to tubular cells and organelles: the application of nanodrugs in acute kidney injury, Nanomedicine Lond. (2023). http://doi.org/10.2217/nnm-2023-0200.

[52] H. Nee Geo, D. Devi Murugan, Z. Chik, A. Norazit, Y. Yee Foo, B. Fen Leo, Y. Yin Teo, S. Zamiah Syed Binti Syed Abdul Kadir, Y. Chan, H. Juang Chai, M. Medel, N. Azizan Abdullah, E. J Johns, M. J Vicent, L. Yong Chung, L. Voon Kiew, Renal nano-drug delivery for acute kidney injury: current status and future perspectives, J. Contr. Release 343 (2022) 237-254. https://doi.org/10.1016/j.jconrel.2022.01.033.

[53] X. Zhao, J. Sun, J. Dong, C. Guo, W. Cai, J. Han, H. Shen, S. Lv, R. Zhang, An autophotoacoustic melanin-based drug delivery nano-platform for self-monitoring of acute kidney injury therapy via a triple-collaborative strategy, Acta, Biomater 147 (2022) 327-341. https://doi.org/10.1016/j.actbio.2022.05.034.

[54] Nazila Kamaly C. Omid, Farokhzad, Nanomedicines for renal disease: current status and future applications, Nat. Rev. Nephrol. 12 (2016) 738-753. https://doi.org/10.1038/nrneph.2016.156.

[55] F. Tong, J. Liu, L. Luo, L. Qiao, J. Wu, G. Wu, Q. Mei, pH/ROS-responsive propelled nanomotors for the active treatment of renal injury, Nanoscale 15 (2023) 6745-6758. https://doi.org/10.1039/D3NR00062A.

[56] L. Zhang, J. J Abbott, L. Dong, K. E Peyer, B. E Kratochvil, H. Zhang, C. Bergeles, B. J Nelson, Characterizing the swimming properties of artificial bacterial flagella, Nano Lett. 9 (2009) 3663-3667. https://doi.org/10.1021/nl901869j.

[57] M. Medina-Sánchez, O.G. Schmidt, Medical microbots need better imaging and control, Nature 545 (2017) 406-408. https://doi.org/10.1038/545406a.

[58] W. Gao, S. Sattayasamitsathit, K. Manian Manesh, D. Weihs, J. Wang, Magnetically powered flexible metal nanowire motors, J. Am. Chem. Soc. 132 (2010) 14403-14405. https://doi.org/10.1021/ja1072349.

[59] Y. Wu, Z. Wu, X. Lin, Q. He, J. Li, Autonomous movement of controllable assembled Janus capsule motors, ACS Nano 6 (2012) 10910-10916. https://doi.org/10.1021/nn304335x.

[60] D. Wilson, R. Nolte, J. van Hest, Autonomous movement of platinum-loaded stomatocytes, Nat. Chem. 4 (2012) 268-274. https://doi.org/10.1038/nchem.1281.

[61] F. Peng, Y. Tu, D. Wilson, Micro/nanomotors towards in vivo application:cell, tissue and biofluid, Chem. Soc. Rev. 46 (2017) 5289-5310. https://doi.org/10.1039/C6CS00885B.

[62] J. Wang, W. Gao, Nano/microscale motors: biomedical opportunities and challenges, ACS Nano 6 (2012) 5745-5751. https://doi.org/10.1021/nn3028997.

[63] J. Parmar, D. Vilela, K. Villa, J. Wang, S. Sánchez, Micro- and nanomotors as active environmental microcleaners and sensors, J. Am. Chem. Soc. 140 (2018) 9317-9331. https://doi.org/10.1021/jacs.8b05762.

[64] W. Gao, J. Wang, Synthetic micro/nanomotors in drug delivery, Nanoscale 6 (2014) 10486-10494. https://doi.org/10.1039/C4NR03124E.

[65] F. Peng, Y. Tu, J. van Hest, D. A Wilson, Self-guided supramolecular cargo-loaded nanomotors with chemotactic behavior towards cells, Angew. Chem. Int. Edit. 54 (2015) 11662-11665. https://doi.org/10.1002/anie.201504186.

[66] F. Peng, Y. Tu, A. Adhikari, J. C, J. Hintzen, P.M. W, D. Löwik, D. A Wilson, A peptide functionalized nanomotor as an efficient cell penetrating tool, Chem. Commun. 53 (2017) 1088-1091. https://doi.org/10.1039/C6CC09169E.

[67] A. Hortelao, T. Patino, A. Perez-Jimenez, A. Blanco, S. Sanchez, Enzyme-powered nanobots enhance anticancer drug delivery, Adv. Funct. Mater. 28 (2017) 1705086. https://doi.org/10.1002/adfm.201705086.

[68] E. Gultepe, J. S Randhawa, S. Kadam, S. Yamanaka, F. M Selaru, E. J Shin, A. N Kalloo, D. H Gracias, Biopsy with thermally-responsive untethered microtools, Adv. Mater. 25 (2013) 514-519. https://doi.org/10.1002/adma.201203348.

[69] H. Xu, M. Medina-Sánchez, V. Magdanz, L. Schwarz, F. Hebenstreit, O.G. Schmidt, Sperm-hybrid micromotor for targeted drug delivery, ACS Nano 12 (2018) 327-337. https://doi.org/10.1021/acsnano.7b06398.

[70] F. Mou, C. Chen, Q. Zhong, Y. Yin, H. Ma, J. Guan, Autonomous Motion and temperature-controlled drug delivery of Mg/Pt-Poly(N-isopropylacrylamide) Janus micromotors driven by simulated body fluid and blood plasma, ACS. Appl. Mater. Interfaces 6 (2014) 9897. https://doi.org/10.1021/am502729y.

[71] T. Xu, W. Gao, L.P. Xu, X. Zhang, S. Wang, Fuel-free synthetic micro-/ nanomachines, Adv. Mater. 29 (2017) 1603250. https://doi.org/10.1002/adma.201603250.

[72] E. Karshalev, B. de ávila, M. Beltrán-Gastélum, P. Angsantikul, S. Tang, R. Mundaca-Uribe, F. Zhang, J. Zhao, L. Zhang, J. Wang, Micromotor pills as a dynamic oral delivery platform, ACS Nano 12 (2018) 8397-8405. https://doi.org/10.1021/acsnano.8b03760.

[73] J. Li, S. Thamphiwatana, W. Liu, B. de ávila, P. Angsantikul, E. Sandraz, J. Wang, T. Xu, F. Soto, V. Ramez, X. Wang, W. Gao, L. Zhang, J. Wang, Enteric micromotor can selectively position and spontaneously propel in the gastrointestinal tract, ACS Nano 10 (2016) 9536-9542. https://doi.org/10.1021/acsnano.6b04795.

[74] B.E. de ávila, P. Angsantikul, J. Li, M. Angel Lopez-Ramirez, D.E. Ramírez- Herrera, S. Thamphiwatana, C. Chen, J. Delezuk, R. Samakapiruk, V. Ramez, M. Obonyo, L. Zhang, J. Wang, Micromotor-enabled active drug delivery for in vivo treatment of stomach infection, Nat. Commun. 8 (2017) 272. https://doi.o rg/10.1038/s41467-017-00309-w.

[75] W. Gao, R. Dong, S. Thamphiwatana, J. Li, W. Gao, L. Zhang, J. Wang, Artificial micromotors in the mouse’s stomach: a step toward in vivo use of synthetic motors, ACS Nano 9 (2015) 117-123. https://doi.org/10.1021/nn507097k.

[76] Z. Wu, J. Troll, H. Jeong, Q. Wei, M. Stang, F. Ziemssen, Z. Wang, M. Dong, S. Schnichels, T. Qiu, P. Fischer, A swarm of slippery micropropellers penetrates the vitreous body of the eye, Sci. Adv. 4 (2018) eaat4388. https://doi.org/10.1126/sciadv.aat4388.

[77] K. Liu, Q. Liu, J. Yang, C. Xie, S. Wang, F. Tong, J. Gao, L. Liu, Y. Ye, B. Chen, X. Cai, Z. Liu, Zeqi Li, F. Peng, Y. Tu, Micromotor based mini-tablet for oral delivery of insulin, ACS Nano 17 (2023) 300-311. https://doi.org/10.1021/acsnano.2c07953.

[78] J. Li, B. de ávila, W. Gao, L. Zhang, J. Wang, Micro/nanorobots for biomedicine: delivery, surgery, sensing, and detoxification, Sci. Robot. 2 (2017) eaam6431. https://doi.org/10.1126/scirobotics.aam6431.

[79] J. Ou, H. Tian, J. Wu, J. Gao, J. Jiang, K. Liu, S. Wang, F. Wang, F. Tong, Y. Ye, L. Liu, B. Chen, X. Ma, X. Chen, F. Peng, Y. Tu, MnO2-based nanomotors with active fenton-like Mn2þ delivery for enhanced chemodynamic therapy, ACS Appl. Mater. Interfaces 13 (2021) 38050-38060. https://doi.org/10.1021/acsami.1c08926.

[80] C. Xu, S. Wang, H. Wang, K. Liu, S. Zhang, B. Chen, H. Liu, F. Tong, F. Peng, Y. Tu, Y. Li, Magnesium-based micromotors as hydrogen generators for precise rheumatoid arthritis therapy, Nano Lett. 21 (2021) 1982-1991. https://doi.org/10.1021/acs.nanolett.0c04438.

[81] B. Chen, L. Liu, K. Liu, F. Tong, S. Wang, D. Fu, J. Gao, J. Jiang, J. Ou, Y. Ye, D. Wilson, Y. Tu, F. Peng, Photoelectrochemical TiO2-Au-nanowire-based motor for precise modulation of single-neuron activities, Adv. Funct. Mater. (2021) 2008667. https://doi.org/10.1002/adfm.202008667.

[82] S. Wang, K. Liu, Q. Zhou, C. Xu, J. Gao, Z. Wang, F. Wang, B. Chen, Y. Ye, J. Ou, J. Jiang, D. Wilson, S. Liu, F. Peng, Y. Tu, Hydrogen-powered microswimmers for precise and active hydrogen therapy towards acute ischemic stroke, Adv. Funct. Mater. 31 (2021) 2009475. https://doi.org/10.1002/adfm.202009475.

[83] K. Liu, Q. Liu, J. Yang, C. Xie, S. Wang, F. Tong, J. Gao, L. Liu, Y. Ye, B. Chen, X. Cai, Z. Liu, Z. Li, F. Peng, Y. Tu, Micromotor based mini-tablet for oral delivery of insulin, ACS Nano 17 (2023) 300-311. https://doi.org/10.1021/acsnano.2c07953.

[84] B. Du, M. Yu, J. Zheng, Transport and interactions of nanoparticles in the kidneys, Nat. Rev. Mater. 3 (2018) 358-374. https://doi.org/10.1038/s41578-018-0038-3.

[85] M.I. Setyawati, C.Y. Tay, S.L. Chia, S.L. Goh, W. Fang, M.J. Neo, H.C. Chong, S.M. Tan, S.C. Loo, K.W. Ng, J.P. Xie, C.N. Ong, N.S. Tan, D.T. Leong, Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE-cadherin, Nat. Commun. 4 (2013) 1673. https://doi.org/10.1038/ncomms2655.

[86] J. Xu, M. Yu, P. Carter, E. Hernandez, A. Dang, P. Kapur, J.T. Hsieh, J. Zheng, In vivo X-ray imaging of transport of renal clearable gold nanoparticles in the kidneys, Angew. Chem. Int. Ed. Engl. 56 (2017) 13356-13360. https://doi.org/10.1002/anie.201707819.

[87] F. Peng, M.I. Setyawati, J.K. Tee, X. Ding, J. Wang, M.E. Nga, H.K. Ho, D.T. Leong, Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness, Nat. Nanotechnol. 14 (2019) 279-286. https://doi.org/10.1038/s41565-018-0356-z.

[88] Y. Huang, J. Wang, K. Jiang, E.J. Chung, Improving kidney targeting: the influence of nanoparticle physicochemical properties on kidney inter actions, J. Contr. Release 334 (2021) 127-137. https://doi.org/10.1016/j.jconrel.2021.04.016.

[89] G. Singh, J.L.Z. Ddungu, N. Licciardello, R. Bergmann, L. De Cola, H. Stephan, Ultrasmall silicon nanoparticles as a promising platform for multimodal imaging, Faraday Discuss 222 (2020) 362-383. https://doi.org/10.1039/C9FD00091G.

[90] S. Li, Y.C. Zeng, K. Peng, C. Liu, Z.R. Zhang, L. Zhang, Design and evaluation of glomerulus mesangium- targeted peg- plga nanoparticles loaded with dexamethasone acetate, Acta, Pharmacol. Sin. 40 (2019) 143-150. https://doi.org/10.1038/s41401-018-0052-4.

[91] H. Yu, T. Lin, W. Chen, W. Cao, C. Zhang, T. Wang, M. Ding, S. Zhao, H. Wei, H. Guo, X. Zhao, Size and temporal- dependent efficacy of oltipraz- loaded plga nanoparticles for treatment of acute kidney injury and fibrosis, Biomaterials 219 (2019) 119368. https://doi.org/10.1016/j.biomaterials.2019.119368.

[92] T.T. Tang, B. Wang, M. Wu, Z.L. Li, Y. Feng, J.Y. Cao, D. Yin, H. Liu, R.N. Tang, S.D. Crowley, L.L. Lv, B.C. Liu, Extracellularvesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI, Sci. Adv. 33 (2020) eaaz0748. https://doi. org/10.1126/sciadv.aaz0748.

[93] A. Czopek, R. Moorhouse, P.J. Gallacher, D. Pugh, J.R. Ivy, T.E. Farrah, E. Godden, R.W. Hunter, D.J. Webb, P.L. Tharaux, D.C. Kluth, J.W. Dear, M.A. Bailey, N. Dhaun, Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice, Sci. Transl. Med. 14 (2022) eabf5074. https://doi.org/10.1126/scitranslmed.abf5074.

[94] L. Yang, B. Wang, F. Guo, R. Huang, Y. Liang, L. Li, S. Tao, T. Yin, P. Fu, L. Ma, FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury, Signal. Transduct. Target. Ther. 7 (2022) 384. https://doi.org/10.1038/s41392-022-01254-x.

[95] W. Yao, Y. Chen, Z. Li, J. Ji, A. You, S. Jin, Y. Ma, Y. Zhao, J. Wang, L. Qu, H. Wang, C. Xiang, S. Wang, G. Liu, F. Bai, L. Yang, Single cell RNA sequencing identifies a unique inflammatory macrophage subset as a druggable target for alleviating acute kidney injury, Adv. Sci. 9 (2022) e2103675. https://doi.org/10.1002/advs.202103675.

[96] O. Esteban, D. Christ, D. Stock, Purification of molecular machines and nanomotors using phage-derived monoclonal antibody fragments, Methods Mol. Biol. 996 (2013) 203-217. https://doi.org/10.1007/978-1-62703-354-1_12.

[97] S.R. Casjens, The DNA-packaging nanomotor of tailed bacteriophages, Nat. Rev. Microbiol. 9 (2011) 647-657. https://doi.org/10.1038/nrmicro2632.

[98] L. Wang, X. Hao, Z. Gao, Z. Yang, Y. Long, M. Luo, J. Guan, Artificial nanomotors: fabrication, locomotion characterization, motion manipulation, and biomedical applications, Interdisciplinary, Materials 2 (2022) 256-280. https://doi.org/10.1002/idm2.12021.

[99] J. Xu, Y. Zhong, W. Wang, R. Gao, Y. Wang, F. Tong, J. Sun, M. Hong, L. Qiao, W. Qiao, Q. Mei, J. Wu, H₂O₂-stimulated Janus-shaped self-propelled nanomotors as an active treatment for acute renal injury, Nanoscale 16 (2024) 1282-1290. https://doi.org/10.1039/D3NR04808J.

[100] J. Yong, A.S. Mellick, J. Whitelock, J. Wang, K. Liang, A biomolecular toolbox for precision nanomotors, Adv. Mater. 35 (2023) e2205746. https://doi.org/10.1002/adma.202205746.

[101] P. Shende, P. Sharma, Current status and emerging trend of nanoshuttle in biological applications, Curr. Pharm. Des. 27 (2021) 105-114. https://doi.org/10.2174/1381612826666200713170356.

[102] S. Shivalkar, P. Chowdhary, T. Afshan, S. Chaudhary, A. Roy, S.K. Samanta, A.K. Sahoo, Nanoengineering of biohybrid micro/nanobots for programmed biomedical applications, Colloids Surf. B Biointerfaces 222 (2023) 113054. https://doi.org/10.1016/j.colsurfb.2022.113054.

[103] Y. Ye, F. Tong, S. Wang, J. Jiang, J. Gao, L. Liu, K. Liu, F. Wang, Z. Wang, J. Ou, B. Chen, D.A. Wilson, Y. Tu, F. Peng, Apoptotic Tumor DNA activated nanomotor chemotaxis, Nano Lett. 21 (2021) 8086-8094. https://doi.org/10.1021/acs.nanolett.1c02441.

[104] Y. Liu, Y. Cheng, C. Zhao, H. Wang, Y. Zhao, Nanomotor-derived porous biomedical particles from droplet microfluidics, Adv. Sci. 9 (2022) e2104272. https://doi.org/10.1002/advs.202104272.

[105] S. Shivalkar, A. Roy, S. Chaudhary, S.K. Samanta, P. Chowdhary, A.K. Sahoo, Strategies in design of self-propelling hybrid micro/nanobots for bioengineering applications, Biomed. Mater. (2023). http://doi.org/10.1088/1748-605X/acf975.

[106] H. Tian, J. Ou, Y. Wang, J. Sun, J. Gao, Y. Ye, R. Zhang, B. Chen, F. Wang, W. Huang, H. Li, L. Liu, C. Shao, Z. Xu, F. Peng, Y. Tu, Bladder microenvironment actuated proteomotors with ammonia amplification for enhanced cancer treatment, Acta Pharm. Sin. B 13 (2023) 3862-3875. https://doi.org/10.1016/j.apsb.2023.02.016.

[107] Q. Li, L. Liu, H. Huo, L. Su, Y. Wu, H. Lin, X. Ge, J. Mu, X. Zhang, L. Zheng, J. Song, Nanosized Janus AuNR-Pt motor for enhancing NIR-II photoacoustic imaging of deep tumor and Pt²⁺ Ion-based chemotherapy, ACS Nano 16 (2022) 7947-7960. https://doi.org/10.1021/acsnano.2c00732.

[108] F. Haque, J. Lunn, H. Fang, D. Smithrud, P. Guo, Real-time sensing and discrimination of single chemicals using the channel of phi29 DNA packaging nanomotor, ACS Nano 6 (2012) 3251-3261. https://doi.org/10.1021/nn3001615.

[109] H. Fang, P. Zhang, L.P. Huang, Z. Zhao, F. Pi, C. Montemagno, P. Guo, Binomial distribution for quantification of protein subunits in biological nanoassemblies and functional nanomachines, Nanomedicine 10 (2014) 1433-1440. https://doi.org/10.1016/j.nano.2014.03.005.

[110] M. Chen, E. Ma, Y. Xing, H. Xu, L. Chen, Y. Wang, Y. Zhang, J. Li, H. Wang, S. Zheng, Dual-modal lateral flow test strip assisted by near-infrared-powered nanomotors for direct quantitative detection of circulating microrna biomarkers from serum, ACS Sens. 8 (2023) 757-766. https://doi.org/10.1021/acssensors.2c02315.

[111] T. Li, M. Sun, Q. Zhou, P. Liang, T. Huang, M. Guo, B. Xie, C. Li, M. Li, W.J. Duan, J.X. Chen, Z. Dai, J. Chen, Endogenous enzyme-powered DNA nanomotor operating in living cells for microrna imaging, Anal. Chem. (2023). https://doi.org/10.1021/acs.analchem.3c03012.

[112] D. Fu, Z. Wang, Y. Tu, F. Peng, Interactions between biomedical micro-/nanomotors and the immune molecules, immune cells, and the immune system: challenges and opportunities, Adv. Healthcare Mater. 10 (2021) e2001788. https://doi.org/10.1002/adhm.202001788.