Recent Advances in Membrane-Coated Micro/Nanomotors in Biological Applications

Abstract

The integration of synthetic micro/nanomotors (MNMs) with natural biomaterials derived from cell membranes has emerged as a highly promising strategy for advancing biological applications. The membrane-coated MNM offers distinct advantages over earlier MNMs dependent on chemical fuels such as hydrogen peroxide, which were prone to poor biocompatibility and harmful byproducts. These include enhanced biocompatibility, immune evasion via natural membrane surfaces, multifunctionality for drug delivery, self-propulsion in complex environments, self-degradation to reduce residual toxicity and inherent imaging capabilities enabling real-time tracking. This review provides a comprehensive overview of the integration of various types of micromotors with natural cell membranes commonly present in the circulatory system. Additionally, it summarizes the methodologies for the preparation, characterization and functional evaluation of biofilm-modified micromotors. The present article also critically examines current developments in biofilm-modified micromotors, addressing their challenges and limitations in enhancing clinical efficacy and facilitating transition to clinical trials in humans.

Keywords: drug delivery; membrane-coated; micro/nanomotors; nanodrugs; self-propulsion.

Graphical abstract

Figure 1

RBC membrane-functionalized micromotors. (A) RBC-based magnetic-driven MNMs for toxin neutralization. Reproduced from Wu Z, Li T, Li J, et al. Turning erythrocytes into functional micromotors. ACS Nano. 2014;8(12):12041–12048. Copyright © 2014 American Chemical Society. (B) RBC-Mg Janus MNMs for toxin absorption. Reproduced from Wu Z, Li J, de Avila BE-F, et al. Water-powered cell-mimicking janus micromotor. Adv Funct Mater. 2015;25(48):7497–7501. Copyright © 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (C) RBC was mimicking rod-like MNMs for toxins neutralization. Reproduced from Wu Z, Li T, Gao W, et al. Cell-membrane-coated synthetic nanomotors for effective biodetoxification. Adv Funct Mater. 2015;25(25):3881–3887. Copyright © 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (D) RBC-based bacterial microswimmer. Reproduced from Alapan Y, Yasa O, Schauer O, et al. Soft erythrocyte-based bacterial microswimmers for cargo delivery. Sci Rob. 2018;3(17):eaar4423. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. (E) RBC-PFC MNMs for oxygen transport. a) The assembly process of RBC-PFC MNMs. b) The detailed structural diagram of RBC-PFC MNMs and their simulated effects in the intestine. Reproduced from Zhang F, Zhuang J, de Avila BEF, et al. A nanomotor-based active delivery system for intracellular oxygen transport. ACS Nano. 2019;13(10):11996–12005. Copyright © 2019 American Chemical Society. (F) RBC membrane-coated Mg-Tio₂ MNMs as an oral antitoxicity vaccine. Reproduced from Wei X, Beltrán-Gastélum M, Karshalev E, et al. Biomimetic micromotor enables active delivery of antigens for oral vaccination. Nano Lett. 2019;19(3):1914–1921. Copyright © 2019 American Chemical Society.

Figure 2

Leukocyte membrane-functionalized MNMs. (A) Mφ-Mg hybrid MNMs for toxin absorption. Reproduced from Zhang F, Mundaca-Uribe R, Gong H, et al. A macrophage-magnesium hybrid biomotor: fabrication and characterization. Adv Mater. 2019;31(27):e1901828. Copyright © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (B) NA@MEV MNMs for cardiac repair and regeneration. Reproduced from Zhang N, Fan M, Zhao Y, et al. Biomimetic and NOS-responsive nanomotor deeply delivery a combination of MSC-EV and mitochondrial ROS scavenger and promote heart repair and regeneration. Adv Sci. 2023;10(21):e2301440. Copyright © 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH. Creative Commons CC BY license. (C) EM@MNMs-loaded neutrophil MNMS for drug delivery. i) Preparation and synthesis of EM vesicles. ii) Preparation of EM@MSNs via vesicle fusion strategy. iii) Co-incubate EM@MSNs with neutrophils to prepare hybrid neutrophil micromotors. Reproduced from Shao J, Xuan M, Zhang H, Lin X, Wu Z, He Q. Chemotaxis-guided hybrid neutrophil micromotors for targeted drug transport. Angew Chem Int Ed Engl. 2017;56(42):12935–12939. Copyright © 2017 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. (D) Neutrophils-membraned EM@nanogels MNMs for blood-brain-barrier crossing. Reproduced from Zhang H, Li Z, Gao C, et al. Dual-responsive biohybrid neutrobots for active target delivery. Sci Rob. 2021;6(52). Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Figure 3

PLT membrane-functionalized micromotors. (A) PLT-based magnetic-driven MNMs for toxin neutralization and bacteria separation. i) Pd/Cu co-electrodeposition in polycarbonate membrane pores (pore size: 400 nm). ii) Removal of Cu phase by nitric acid etching and release of helical Pd nanomotors. iii) Ni/Au bilayer deposition on the surface of pd helical nanostructures. iv) Collection and separation of helical nanomotors. v) Modification of the surface of bare helical nanomotors with 3 - mercaptopropionic acid (MPA). vi) Anchoring of PL-vesicles to the surface of MPA-modified helical nanomotors. Reproduced from Li J, Angsantikul P, Liu W, et al. Biomimetic platelet-camouflaged nanorobots for binding and isolation of biological threats. Adv Mater. 2018;30(2):1704800. Copyright © 2017 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (B) RBC-PL hybrid MNMs for detoxification. i) Modification of the gold surface of gold nanowire (AuNW) Robots with MPA. ii) Preparation of hybrid membrane by fusing erythrocyte membrane and platelet membrane at a 1:1 protein mass ratio and its coating of MPA - modified nanorobots. iii) Preparation of red blood cell-platelet membrane robots (RBC-PL-robots) by 5 minutes ultrasonication. Reproduced from Esteban-Fernández de Ávila B, Angsantikul P, Ramírez-Herrera DE, et al. Hybrid biomembrane-functionalized nanorobots for concurrent removal of pathogenic bacteria and toxins. Sci Rob. 2018;3(18). Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. (C) Urease-catalyzed JPL-Motor for chemotherapeutic agent carrier. Reproduced from Tang S, Zhang F, Gong H, et al. Enzyme-powered Janus platelet cell robots for active and targeted drug delivery. Sci Rob. 2020;5(43). Copyright © 2020, Science Robotics. (D) PLT@PDA-DOX MNMs for targeted cancer therapy. Reproduced from Li T, Chen T, Chen H, et al. Engineered platelet-based micro/nanomotors for cancer therapy. Small. 2021;17(52):e2104912. Copyright © 2021 Wiley‐VCH GmbH.

Figure 4

(A) Gold nanoshells modified CaCO₃ MNMs for anti-tumor immunity. Reproduced from Zhang H, Li Z, Wu Z, He Q. Cancer Cell Membrane Camouflaged Micromotor. Adv Ther. 2019;2(12):1900096. Copyright © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (B) MC@SiO₂ @DOXMNMs for drug loading. Reproduced from Zhou M, Xing Y, Li X, Du X, Xu T, Zhang X. Cancer cell membrane camouflaged semi-yolk@spiky-shell nanomotor for enhanced cell adhesion and synergistic therapy. Small. 2020;16(39):e2003834. Copyright © 2020 Wiley‐VCH GmbH. (C) 4T1 cell-coated mesoporous gold nanospheres for tumor photothermal therapy. Reproduced from Wang H, Gao J, Xu C, et al. Light-driven biomimetic nanomotors for enhanced photothermal therapy. Small. 2023;e2306208. Copyright © 2023 Wiley‐VCH GmbH.

Figure 5

MNMs for Thrombosis treatment. (A) JAMS/PTX/AV combined with DBC for atherosclerosis treatment. Reproduced from Huang Y, Li T, Gao W, et al. Platelet-derived nanomotor coated balloon for atherosclerosis combination therapy. J Mater Chem B. 2020;8(26):5765–5775. Copyright © 2020, Journal of Materials Chemistry. (B) RBC-membraned MNMs with gold shells for atherosclerosis treatment. Reproduced from Shao J, Abdelghani M, Shen G, Cao S, Williams DS, van Hest JCM. Erythrocyte membrane modified janus polymeric motors for thrombus therapy. ACS Nano. 2018;12(5):4877–4885. Copyright © 2018 American Chemical Society. (C) INR-driven MMNM/Hep/UK/PM for venous thrombosis treatment. Reproduced from Wan M, Wang Q, Wang R, et al. Platelet-derived porous nanomotor for thrombus therapy. Sci Adv. 2020;6(22):eaaz9014. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). Copyright 2020, Science Advances. (D) GOX-driven and uPA-loaded MNMs for venous thrombolysis. Reproduced from Fang X, Ye H, Shi K, et al. GOx-powered janus platelet nanomotors for targeted delivery of thrombolytic drugs in treating thrombotic diseases. ACS Biomater Sci Eng. 2023;9(7):4302–4310. Copyright © 2023 American Chemical Society.

Figure 6

MNMs for Tumor Imaging and precise on-demand drug delivery. (A) Macrophage-cell-membrane-coated MNMs for the thermomechanical portion of cancer cell membranes. a) Schematic diagram of the preparation process of MPCM@JMSNMs. b) SEM image of JMSNMs. Inset: TEM image of a Single JMSNM. Reproduced from Xuan M, Shao J, Gao C, Wang W, Dai L, He Q. Self-propelled nanomotors for thermomechanically percolating cell membranes. Angew Chem Int Ed Engl. 2018;57(38):12463–12467. Copyright © 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. (B) Needle-like white cell membrane-coated gallium MNMs for Photothermal Therapy. Reproduced from Wang D, Gao C, Zhou C, Lin Z, He Q. Leukocyte membrane-coated liquid metal nanoswimmers for actively targeted delivery and synergistic chemophotothermal therapy. Research. 2020;2020:3676954. Copyright © 2020 Daolin Wang et al. C) Magnetic anticancer DOX@MPN for chemo-phototherapy. Reproduced from Song X, Qian R, Li T, et al. Imaging-Guided biomimetic M1 macrophage membrane-camouflaged magnetic nanorobots for photothermal immunotargeting cancer therapy. ACS Appl Mater Interfaces. 2022;14(51):56548–56559. Copyright © 2022 American Chemical Society. (D) RBC-based and Fe₃O₄-encapsulated hemoglobin MNMs for oxygen and PSs activity delivery. Reproduced from Gao C, Lin Z, Wang D, Wu Z, Xie H, He Q. Red blood cell-mimicking micromotor for active photodynamic cancer therapy. ACS Appl Mater Interfaces. 2019;11(26):23392–23400. Copyright © 2019 American Chemical Society. (E) Multi-cargo-loaded RBC micromotors for imaging. Reproduced from Wu Z, de Avila BE-F, Martin A, et al. RBC micromotors carrying multiple cargos towards potential theranostic applications. Nanoscale. 2015;7(32):13680–13686. Copyright © The Royal Society of Chemistry 2015. (F) Bio-RBC-based MNMs as a potential mobile thermal therapy and imaging tool. Reproduced from Hou K, Zhang Y, Bao M, et al. A multifunctional magnetic red blood cell-mimetic micromotor for drug delivery and image-guided therapy. ACS Appl Mater Interfaces. 2022;14(3):3825–3837. Copyright © 2022 American Chemical Society.

Figure 7

MNMs for neurological disorders. (A) macrophage membrane-cloaked nanomotor for neuroinflammation therapy. Reproduced from Ye J, Fan Y, She Y, et al. Biomimetic self-propelled asymmetric nanomotors for cascade-targeted treatment of neurological inflammation. Adv Sci. 2024;11(22):2310211. Copyright © 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH. Creative Commons CC BY license. (B) dual-driven nanomotor for glioblastoma. Reproduced from Ye J, Fan Y, Kang Y, et al. Biomimetic dual-driven heterojunction nanomotors for targeted catalytic immunotherapy of glioblastoma. Adv Funct Mater. 2025;35(9):2416265. Copyright © 2024 Wiley‐VCH GmbH.

Figure 8

MNMs for acute Bacterial Pneumonia treatment. (A) Algae-neutrophil hybrid MNMs are used for antibiotic transport. Reproduced from Zhang F, Zhuang J, Li Z, et al. Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia. Nat Mater. 2022;21(11):1324–1332. Copyright © 2022 Nature Materials.. (B) Macrophage-based MNMs for anti-inflammation. Reproduced from Yue L, Gao C, Li J, et al. Chemotaxis-guided self-propelled macrophage motor for targeted treatment of acute pneumonia. Adv Mater. 2023;35(20):e2211626. Copyright © 2023 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.