Bioengineered and biohybrid bacteria-based systems for drug delivery

Phagocytosis is a principal component of the body's innate immunity in which macrophages internalize targets in an actin-dependent manner. Targets vary widely in shape and size and include particles such as pathogens and senescent cells. Despite considerable progress in understanding this complicated process, the role of target geometry in phagocytosis has remained elusive. Previous studies on phagocytosis have been performed using spherical targets, thereby overlooking the role of particle shape. Using polystyrene particles of various sizes and shapes, we studied phagocytosis by alveolar macrophages. We report a surprising finding that particle shape, not size, plays a dominant role in phagocytosis. All shapes were capable of initiating phagocytosis in at least one orientation. However, the local particle shape, measured by tangent angles, at the point of initial contact dictates whether macrophages initiate phagocytosis or simply spread on particles. The local shape determines the complexity of the actin structure that must be created to initiate phagocytosis and allow the membrane to move over the particle. Failure to create the required actin structure results in simple spreading and not internalization. Particle size primarily impacts the completion of phagocytosis in cases where particle volume exceeds the cell volume.

The motion of an artificial micro-scale swimmer that uses a chemical reaction catalyzed on its own surface to achieve autonomous propulsion is fully characterized experimentally. It is shown that at short times, it has a substantial component of directed motion, with a velocity that depends on the concentration of fuel molecules. At longer times, the motion reverts to a random walk with a substantially enhanced diffusion coefficient. Our results suggest strategies for designing artificial chemotactic systems.

Oxygen depleted hypoxic regions in the tumour are generally resistant to therapies 1 . Although nanocarriers have been used to deliver drugs, the targeting ratios have been very low. Here, we show that the magneto-aerotactic migration behaviour 2 of magnetotactic bacteria 3 , Magnetococcus marinus strain MC-1 4 , can be used to transport drug-loaded nanoliposomes into hypoxic regions of the tumour. In their natural environment, MC-1 cells, each containing a chain of magnetic iron-oxide nanocrystals 5 , tend to swim along local magnetic field lines and towards low oxygen concentrations 6 based on a two-state aerotactic sensing system 2 . We show that when MC-1 cells bearing covalently bound drug-containing nanoliposomes were injected near the tumour in SCID Beige mice and magnetically guided, up to 55% of MC-1 cells penetrated into hypoxic regions of HCT116 colorectal xenografts. Approximately 70 drug-loaded nanoliposomes were attached to each MC-1 cell. Our results suggest that harnessing swarms of microorganisms exhibiting magneto-aerotactic behaviour can significantly improve the therapeutic index of various nanocarriers in tumour hypoxic regions.