Abstract
Biohybrid microswimmers, which are realized through the integration of motile microscopic organisms with artificial cargo carriers, have a significant potential to revolutionize autonomous targeted cargo delivery applications in medicine. Nonetheless, there are many open challenges, such as motility performance and immunogenicity of the biological segment of the microswimmers, which should be overcome before their successful transition to the clinic. Here, we present the design and characterization of a biohybrid microswimmer, which is composed of a genetically engineered peritrichously flagellated Escherichia coli species integrated with red blood cell-derived nanoliposomes, also known as nanoerythrosomes. Initially, we demonstrated nanoerythrosome fabrication using the cell extrusion technique and characterization of their size and functional cell membrane proteins with dynamic light scattering and flow cytometry analyses, respectively. Then, we showed the construction of biohybrid microswimmers through the conjugation of streptavidin-modified bacteria with biotin-modified nanoerythrosomes by using non-covalent streptavidin interaction. Finally, we investigated the motility performance of the nanoerythrosome-functionalized biohybrid microswimmers and compared it with the free-swimming bacteria. The microswimmer design approach presented here could lead to the fabrication of personalized biohybrid microswimmers from patients' own cells with high fabrication efficiencies and motility performances.
Highlights
Fabrication of the nanoerythrosome-functionalized biohybrid microswimmers was realized through the conjugation of streptavidinmodified genetically engineered E. coli MG1655 substrain with biotinmodified nanoerythrosomes [Fig. 1(a)]
Construction of active cargo delivery systems using microorganisms and biological materials, which can be obtained from the human body, presents promising potential to revolutionize various medical operations, including drug delivery and cancer treatment, in hard-toreach body locations
Selection of bioactuators naturally found in the human body, such as E. coli, and cargo carriers, such as red blood cells (RBCs), which could be obtained from patients, is crucial for the development of next-generation biohybrid microswimmers with superior medical characteristics, such as lower immunogenicity, decreased protein corona formation, enhanced circulation time, and navigation inside complex body environments.[1,38,39,48]
Summary
Biohybrid microswimmers are mainly composed of integrated biological actuators and synthetic cargo carriers and have been recently shown to be promising toward minimally invasive theranostic applications.[1,2,3,4] Various microorganisms, including bacteria,[5,6] microalgae,[7,8] and spermatozoids,[9,10] have been utilized to fabricate different biohybrid microswimmers with advanced medical functionalities, such as autonomous control with environmental stimuli for targeting, navigation through narrow gaps, and accumulation to necrotic regions of tumor environments.[11]. Bacteria have a high swimming speed and efficiency in the low Reynolds (Re) number flow regime, are capable of sensing and responding to external environmental signals, and could be externally detected via fluorescence or ultrasound imaging techniques.[19,20,21] Due to their inherent sensing capabilities, various bacteria species have been investigated as potential anti-tumor agents and have been the subject of preclinical and clinical trials.[22,23,24,25,26,27] the presence of different bacteria species in the human body, such as on the skin and the gut microenvironment, has promoted their use as potential theranostic agents or carriers in several medical applications.[28] On the other hand, specialized eukaryotic cells, such as red blood cells (RBCs), are one of the nature’s most efficient passive carriers with high payload
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