Dual-responsive biohybrid neutrobots for active target delivery
Abstract
Swimming biohybrid microsized robots (e.g., bacteria- or sperm-driven microrobots) with self-propelling and navigating capabilities have become an exciting field of research, thanks to their controllable locomotion in hard-to-reach areas of the body for noninvasive drug delivery and treatment. However, current cell-based microrobots are susceptible to immune attack and clearance upon entering the body. Here, we report a neutrophil-based microrobot (“neutrobot”) that can actively deliver cargo to malignant glioma in vivo. The neutrobots are constructed through the phagocytosis of Escherichia coli membrane-enveloped, drug-loaded magnetic nanogels by natural neutrophils, where the E. coli membrane camouflaging enhances the efficiency of phagocytosis and also prevents drug leakage inside the neutrophils. With controllable intravascular movement upon exposure to a rotating magnetic field, the neutrobots could autonomously aggregate in the brain and subsequently cross the blood-brain barrier through the positive chemotactic motion of neutrobots along the gradient of inflammatory factors. The use of such dual-responsive neutrobots for targeted drug delivery substantially inhibits the proliferation of tumor cells compared with traditional drug injection. Inheriting the biological characteristics and functions of natural neutrophils that current artificial microrobots cannot match, the neutrobots developed in this study provide a promising pathway to precision biomedicine in the future.
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Supplementary Material
Summary
Methods
Fig. S1. Characterization of Fe3O4 NPs.
Fig. S2. TEM image of nanogels.
Fig. S3. Dependence of PTX encapsulated in each milligram nanogels on PTX loading amount.
Fig. S4. CLSM images of [email protected]
Fig. S5. Movement of neutrophils incubated in different suspensions.
Fig. S6. Morphological image of neutrophils.
Fig. S7. CLSM images of neutrophils, neutrobots, neutrophils incubated with nanogels to show cell viability.
Fig. S8. RMF navigation system.
Fig. S9. Velocity of neutrobots (nanogels inside) under RMF with different strength and frequency.
Fig. S10. Motion of neutrobots on the substrate and suspended in liquid under RMF (15 mT, 2 Hz).
Fig. S11. Motion of neutrobots under gradient MF (~800 mT).
Fig. S12. Photograph of the model blood flow system using a fresh blood–filled microfluidic.
Fig. S13. Frequency range of neutrobot swarm formation under RMF (18 mT).
Fig. S14. Simulation of neutrobots’ positions in a tetramer swarm in Y and Z axis change with time.
Fig. S15. Schematic layout of Ibidi μ-Slide Chemotaxis3D.
Fig. S16. Scheme illustration of measurement of TAD.
Fig. S17. Chemotactic motion of neutrophils in CG.
Fig. S18. Velocity of neutrobots on the surface of blood vessel and PDMS substrate under RMF (15 mT, 2 Hz).
Fig. S19. Photograph of actual Transwell setup in 24-well plate.
Fig. S20. Schematic and microscope images of neutrophils and neutrobots going through model BBB.
Fig. S21. CLSM images of [email protected] neutrobots before treated with fMLP or PMA.
Fig. S22. CLSM images show neutrobots deliver [email protected] to G422 cells.
Fig. S23. CLSM image of the brain-frozen section of brain harvest from glioma-bearing mouse.
Fig. S24. Helmholtz coil magnetic field device used in animal experiment.
Fig. S25. Targeting ratio of neutrobots to main organs of glioma-bearing mice after different treatment.
Fig. S26. T2-weighted MRI of blood, neutrobots, and magnetic NPs with different concentration.
Fig. S27. Ultrathin-section TEM images of glioma to show neutrobots inside glioma tissue.
Fig. S28. Statistics of neutrobots in the histosection of glioma.
Fig. S29. Change in the body weight of glioma-bearing mice after different treatment.
Fig. S30. Histological observation of main organs collected from glioma-bearing mice after different treatment.
Movie S1. Schematic illustration for synthesis and dual-responsive active delivery of neutrobots.
Movie S2. Motion of multiple neutrobots moving toward a certain direction under RMF (15 mT, 2 Hz).
Movie S3. Motion of neutrobots on the substrate (blue trajectory) and suspended in liquid (green trajectory) under RMF (15 mT, 2 Hz).
Movie S4. Motion of neutrobots with a wave-like trajectory and star-like trajectory under RMF (15 mT, 2 Hz).
Movie S5. Motion of neutrobots under gradient MF (~800 mT).
Movie S6. Motion of neutrobots against flow under RMF.
Movie S7. Formation of chain from mono-neutrobot to tetra-neutrobots under RMF (18 mT, 15 Hz).
Movie S8. Magnetically powered movement of tetra-neutrobot swarm chain under RMF (18 mT, 15 Hz).
Movie S9. Chemotactic motion of neutrobots along CG.
Movie S10. Dual-responded motion of neutrobots on the blood vessel wall.
Movie S11. Neutrobots moving across the BBB model by chemotactic motion.
Reference (59)
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Information & Authors
Information
Published In
Science Robotics
Volume 6 • Issue 52 • 24 March 2021
History
Received: 12 September 2020
Accepted: 26 February 2021
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Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
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Funding Information
National Nature Science Foundation of China: 21972035
Nature Science Foundation of Heilongjiang Providence: YQ2019E018
