Biohybrid Micro- and Nanorobots for Intelligent Drug Delivery

Abstract

Biohybrid micro- and nanorobots are integrated tiny machines from biological components and artificial components. They can possess the advantages of onboard actuation, sensing, control, and implementation of multiple medical tasks such as targeted drug delivery, single-cell manipulation, and cell microsurgery. This review paper is to give an overview of biohybrid micro- and nanorobots for smart drug delivery applications. First, a wide range of biohybrid micro- and nanorobots comprising different biological components are reviewed in detail. Subsequently, the applications of biohybrid micro- and nanorobots for active drug delivery are introduced to demonstrate how such biohybrid micro- and nanorobots are being exploited in the field of medicine and healthcare. Lastly, key challenges to be overcome are discussed to pave the way for the clinical translation and application of the biohybrid micro- and nanorobots.

Scheme 1

Summary of various biohybrid micro- and nanorobots.

Figure 1

(a) Magnetic microswimmers hybridized with DNA flagellar bundles of straight 8HT (A), twisted 8HT (B), and supertwisted 13HT (C). Reproduced with permission from Reference [28]. Copyright 2016, American Chemical Society. (b) Locomotion mechanism of catalase-propelled submarine-like MOF micromotors. Reproduced with permission from Reference [36]. Copyright 2019, Elsevier Ltd. (c) Hybrid RBC-PL-robots for performing medical tasks. Reproduced with permission from Reference [44]. Copyright 2018, The Authors, exclusive licensee American Association for the Advancement of Science.

Figure 2

(a) Macrophage-based biohybrid microrobots for active tumor therapy. Reproduced with permission from Reference [50]. Copyright 2016, The Authors, licensed under a Creative Commons Attribution 4.0 International License. (b) Active drug delivery of dual-responsive neutrobots towards the malignant glioma. ① Active cumulation of neutrobots towards the glioma under an external magnetic field. ② Chemotaxis of neutrobots along the gradient of the inflammatory factors. ③ BBB penetration of neutrobots. ④ Local release of PTX from neutrobots inside the malignant glioma. Note: BBB/BBTB = blood-brain barrier/blood-brain tumor barrier. Reproduced with permission from Reference [56]. Copyright 2021, The Authors, exclusive licensee American Association for the Advancement of Science.

Figure 3

(a) Schematic illustration of magnetically navigated, ultrasonically propelled RBC micromotors in the whole blood. Reproduced with permission from Reference [58]. Copyright 2014, American Chemical Society. (b) Sperm flagella-driven micro-bio-robots. (A) Optical image of a bull spermatozoon. (B, D) SEM images of rolled-up Ti/Fe microtube on glass with a sperm at the opening of tube. (C) Illustrative fabrication of a micro-bio-robot through trapping a motile sperm inside a Ti/Fe microtube for magnetic remote control. (E) Optical image of a sperm (yellow shadow) trapped inside a Ti/Fe microtube (yellow dots). Note: blue arrow = sperm head; red arrow = sperm flagellum. Reproduced with permission from Reference [64]. Copyright 2013, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 4

(a) Bacteria-driven microswimmers on the basis of PEM-MNP microparticles attached to E. coli MG1655 bacteria. (A) Schematic design of bacteria-driven microswimmers for active targeted drug delivery. Note: PS = polystyrene microparticle (1 μm diameter). (B) SEM image of one single PS(MNP₁PAH/PSS)₄PAH-attached bacterium. (C) TEM image of thin section of a microswimmer. Inset: TEM image of monolayer of MNPs. Reproduced with permission from Reference [71]. Copyright 2017, American Chemical Society. (b) Magnetically guided, bacterially driven RBC microswimmers for active drug delivery. Reproduced with permission from Reference [72]. Copyright 2018, The Authors, exclusive licensee American Association for the Advancement of Science.

Figure 5

(a) Spermbots for targeted DOX delivery. (A) Illustration of a microfluidic chip for the transport and delivery of drug-loaded sperm. (B) SEM images indicating the fusion of sperm and HeLa cell. Note: red arrows = a cell in apoptosis; blue arrows = live cells. Reproduced with permission from Reference [79]. Copyright 2017, American Chemical Society. (b) Urease-powered Janus platelet robots for enhanced anticancer/antibacterial activity through loading DOX chemodrug or ciprofloxacin (Cip) antibiotic for active, targeted drug delivery. (A) Schematic illustration of DOX-loaded JPL-motors for targeted delivery to MDA-MB-231 breast cancer cells. (B) Pseudocolored SEM image of multiple JPL-motors (red) attaching to a single cancer cell (purple). (C) Pseudocolored SEM image showing the binding between a Cip-loaded JPL-motor (green) and a single E. coli (red). Reproduced with permission from Reference [60]. Copyright 2020, The Authors, exclusive licensee American Association for the Advancement of Science.

Figure 6

The representative applications of cargo delivery systems versus the size of biohybrid micro- and nanorobots. (a) DNA-based nanorobots for thrombin delivery to tumor-associated blood vessels with the aim to inhibit tumor growth by inducing intravascular thrombosis. Human breast cancer cells (MDA-MB-231) and BALB/c nude mice were used for in vivo experiments. Reproduced with permission from Reference [29]. Copyright 2018, Nature Publishing Group. (b) Enzyme-based nanorobots for transport and stimuli-responsive release of drugs ([Ru(bpy)₃]Cl₂ or doxorubicin DOX). In vitro experiments were conducted by using HeLa cells. Reproduced with permission from Reference [85]. Copyright 2019, American Chemical Society. (c) Erythrocyte-based microrobots for anticancer drug (i.e., DOX) delivery. Reproduced with permission from Reference [86]. Copyright 2020, American Chemical Society. (d) Microalgae (i.e., Chlamydomonas reinhardtii)-based microrobot for anticancer drug (i.e., DOX) delivery. SK-BR-3 breast cancer cells were adopted for in vitro experiments. Reproduced with permission from Reference [76]. Copyright 2020, The Authors. (e) Neutrophil-based microrobots for targeted drug delivery in the brain. Under the navigation of a rotating magnetic field, the microrobots can travel across the blood-brain barrier to inhibit the proliferation of tumor cells by releasing the drugs in targeted sites. Reproduced with permission from Reference [56]. Copyright 2016, The Authors. (f) A magnetotactic bacteria-based microrobot with conjugated nanoliposomes, which has the potential to deliver therapy drugs to hard-to-reach regions in solid tumors via the self-propulsion from the flagella and navigation of external magnetic fields. Reproduced with permission from Reference [87] Copyright 2014, American Chemical Society. (g) Sperm-based micromotors with the loading of doxorubicin hydrochloride for active drug delivery. HeLa cell tumor spheroids were used for in vitro drug delivery experiments performed in a microfluidic channel. Reproduced with permission from Reference [79]. Copyright 2017, American Chemical Society. (h) Macrophage-based magnetic microrobots loaded with docetaxel for active cancer therapy. The in vitro experiments were conducted in a microfluidic channel by using three-dimensional tumor spheroids from 4T1 breast cancer cells or CT26 colorectal carcinoma cells. Reproduced with permission from Reference [50]. Copyright 2016, The Authors. (i) Spirulina-based magnetic helical microrobot loaded with DOX for in vitro cancer therapy via controlled pH- and NIR-triggered drug release mode. The 769-P kidney cancer cells and EC109 esophageal cancer cells are used for in vitro experiments. Reproduced with permission from Reference [88]. Copyright 2019, American Chemical Society. (j) Sperm-based microrobots for heparin (i.e., a type of anticoagulant agent) transport in flowing blood, which have the potential to treat blood clots or other diseases in the circulatory system. Reproduced with permission from Reference [80]. Copyright 2020, American Chemical Society.