Transforming Bacteria into Microrobots for Targeted Drug Delivery in Cancer Treatment

Written by丨Wang Cong

Edited by丨Wang Duoyu

Typeset by丨Shui Chengwen

Bacteria are attracted to chemical gradients, such as low oxygen levels or high acidity, both of which are commonly found near tumor tissues. Injecting bacteria near tumor tissues for cancer treatment is known as bacteria-mediated tumor therapy. The bacteria accumulate in the tumor tissue and grow, activating the patient’s immune system to combat the tumor.

As early as the late 19th century, American surgeon William Coley discovered that bacterial infections could lead to tumor regression and used inactivated bacteria to fight malignant tumors, marking the beginning of cancer immunotherapy in humans.

Escherichia coli is a type of multifunctional bacteria that can swim rapidly and navigate through various materials, from liquids to highly viscous tissues, and they possess highly sensitive sensing capabilities. Over the past few decades, scientists have been looking for ways to further enhance the capabilities of E. coli, hoping to equip them with additional components to help them fight cancer cells.

Recently, researchers at the Max Planck Institute for Intelligent Systems (MPI-IS) in Germany published a research paper titled: Magnetically steerable bacterial microrobots moving in 3D biological matrices for stimuli-responsive cargo delivery in the journal Science Advances.

The study combines robotics with biology, equipping E. coli with artificial components to construct a mobile biomimetic microrobot capable of carrying drug molecules, which can navigate in 3D biological materials under magnetic field guidance and deliver anticancer drugs to tumors.

The corresponding author of the study, Dr. Metin Sitti, stated that medically functional bacteria-based biomimetic microrobots could one day combat cancer more effectively, representing a new method not far from our current cancer treatment approaches. The effects of medical microrobots in locating and destroying tumor cells could be tremendous. This research is also a good example of how basic scientific research benefits society.

Biomimetic microrobots are formed by combining living microorganisms (such as bacteria or algae) with artificial components (such as nanocarriers), creating a self-functional micromachine with intrinsic propulsion, sensing, and targeting mechanisms. Among different types of microrobots, bacteria-driven biomimetic microrobots stand out as ideal candidates for medical microrobot applications.

However, in practice, adding artificial components to bacteria is not an easy task, as it involves complex chemical reactions. Most techniques used to design biomimetic microrobots may adversely affect the bacteria themselves, potentially interfering with their movement or altering their protein expression. Current designs of bacterial biomimetic robots lack high-throughput and easy-to-build artificial components, leading to subpar performance in propulsion, payload, tissue penetration, and spatiotemporal operation.

In this latest study, the research team first connected nanoliposomes to E. coli, with water-soluble chemotherapy drug doxorubicin (DOX) encapsulated inside the nanoliposomes. The phospholipid bilayer of these nanoliposomes also embedded indocyanine green (ICG), a medical fluorescent agent that melts under near-infrared light. Therefore, this is a photothermal active liposome plasmid that, upon absorbing near-infrared light (NIR), causes the ICG embedded in the phospholipid bilayer of the nanoliposomes to melt, leading to structural changes in the liposomes and the release of the therapeutic drug contained within.

The research team also attached magnetic nanoparticles (iron oxide nanoparticles) to the bacteria, allowing these iron oxide nanoparticles to control and propel the movement of E. coli under a magnetic field. Both the nanoliposomes and magnetic nanoparticles are linked to the bacteria using the robust streptavidin-biotin complex.

Next, the research team confirmed in in vitro experiments that this bacterial biomimetic microrobot could be precisely navigated by a magnetic field to release chemotherapy drugs towards the tumor.

Subsequently, the research team further tested in a viscous collagen gel (similar to tumor tissue), and the results showed that under the magnetic field, these bacterial biomimetic microrobots could traverse collagen gels of varying hardness and porosity. This indicates that these bacterial biomimetic microrobots can penetrate and move in constrained and porous biological microenvironments under magnetic field guidance.

Once these microrobots gather around the tumor, near-infrared light (NIR) is used to trigger the melting process of the nanoliposomes and release the chemotherapy drugs they carry. The acidic environment near the tumor with a low pH will also cause the nanoliposomes to rupture, thus releasing the drugs automatically near the tumor.

Imagine injecting these bacteria-based microrobots into cancer patients’ bodies, navigating them to the tumors under magnetic field guidance. Once enough microrobots surround the tumor, near-infrared light can be activated to trigger the release of chemotherapy drugs. This not only awakens the immune system but also helps destroy the tumor by releasing chemotherapy drugs. This delivery method is minimally invasive, painless, and has minimal toxicity for patients, with the drugs acting specifically on the tumor, avoiding harm to other parts of the body.

Overall, the bacterial biomimetic microrobots developed in this latest study outperform previously reported E. coli-based microrobots, retaining the swimming capabilities of E. coli itself while demonstrating the ability to navigate and colonize tumors under magnetic field guidance and subsequently release the loaded anticancer drugs as needed.

In summary, the bacterial biomimetic design introduced here provides a systematic, high-throughput platform for multifunctional medical microrobots that can overcome biological barriers and perform stimuli-responsive active drug release.

Paper Link:

https://www.science.org/doi/10.1126/sciadv.abo6163

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