A biohybrid microswimmer—a genetically engineered bacterium studded with nanoerythrosomes—can be loaded with molecular cargo, injected into the body, and sent on a delivery mission. For example, the microswimmer could propel itself through viscous environments and tissue cells to dispense drugs at a tumor site.

To get where it needs to go, the microswimmer could home in on a signal of some kind. A chemical signal could allow microswimmer dispatchers to take advantage, however passively, of a bacterium’s natural sensing capabilities. Alternatively, magnetic or sound signals could allow for a more active, hands-on approach. That is, microswimmer movements could be subjected to remote control.

These are exciting possibilities. If they are to be realized, however, microswimmers must have adequate carrying capacity, motility, and non-immunogenicity. Endowing microswimmers with the capabilities they need is the self-appointed task of scientists based at the Max Planck Institute for Intelligent Systems. These scientists, led by Metin Sitti, PhD, have described some of their recent advances in a paper (“Nanoerythrosome-functionalized biohybrid microswimmers”) that appeared April 7 in APL Bioengineering.

The paper describes how the researchers fabricated biohybrid bacterial microswimmers by combining a genetically engineered Escherichia coli MG1655 substrain and nanoerythrosomes, small vesicular structures made from red blood cells. Nanoerythrosomes are derived from red blood cells by emptying the cells, keeping the membranes, and filtering them down to nanoscale size.

“We investigated the motility performance of the nanoerythrosome-functionalized biohybrid microswimmers and compared it with the free-swimming bacteria,” the article’s authors wrote. “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.”

The article also described how the nanoerythrosomes were attached to the bacterial membrane using the powerful noncovalent biological bond between biotin and streptavidin. This process preserved two important red blood cell membrane proteins: TER119 needed to attach the nanoerythrosomes, and CD47 to prevent macrophage uptake.

The E. coli MG 1655 serves as a bioactuator performing the mechanical work of propelling through the body as a molecular engine using flagellar rotation. The swimming capabilities of the bacteria were assessed using a custom-built 2D object-tracking algorithm and 20 videos taken as raw data to document their performance.

Illustration (top) and scanning electron microscopy image (bottom) of biohybrid bacterial microswimmers, which were fabricated by combining genetically engineered E. coli MG1655 and nanoerythrosomes made from red blood cells. A biotin-streptavidin interaction was used to attach nanoerythrosomes to the bacterial membrane. [Buss, Yasa, Alapan, Akolpoglu, and Sitti, Max Planck Institute for Intelligent Systems]

Biohybrid microswimmers with bacteria carrying red blood cell nanoerythrosomes performed at speeds 40% faster than other E. coli-powered microparticles-based biohybrid microswimmers, and the work demonstrated a reduced immune response due to the nanoscale size of the nanoerythrosomes and adjustments to the density of coverage of nanoerythrosomes on the bacterial membrane.

These biohybrid swimmers could deliver drugs faster, due to their swimming speed, and encounter less immune response, due to their composition. The researchers plan to continue their work to further tune the immune clearance of the microrobots and investigate how they might penetrate cells and release their cargo in the tumor microenvironment.

“This work is an important stepping stone in our overarching goal of developing and deploying biohybrid microrobots for therapeutic cargo delivery,” declared Sitti, the paper’s corresponding author and director of the physical intelligence department at Max Planck. “If you decrease the size of red blood cells to nanoscale and functionalize the body of the bacteria, you could obtain additional superior properties that will be crucial in the translation of the medical microrobotics to clinics.”

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