Antibiotics are not particularly sophisticated medicines. They simply circulate in the bloodstream or dissolve in the stomach and must exert their influence quickly before being degraded or excreted. For persistent infections, this might not be good enough.

A new invention birthed from a collaboration between two bioengineers makes antibiotics more precise and persistent in the body. Rather than a passive dose of antibiotics, the bioengineers attached the drugs to “microrobots” made of algae. They described their invention in a recent publication in Nature Materials (1). 

“There was a lot of brainstorming and discussion to come up with the idea of algae robots,” said Liangfang Zhang, a bioengineer at the University of California, San Diego (UCSD) and coauthor of the study. 

Previously, scientists coated microscopic pieces of metal, like zinc or copper with antibiotics (2). This approach works for oral antibiotic delivery where nanoparticles pass through the digestive tract before excretion, but it won’t work in parts of the body that are harder to clear. “You cannot leave anything behind in the lungs or other organs,” said Zhang. The team needed a new way to deliver antibiotics.

Zhang’s group landed on algae cells for a few reasons. A microrobot delivery system would need to be big enough to carry a dose of medicine, but small enough to penetrate deep into tissues. Chlamydomonas reinhardtii, a species of algae that is about 10 micrometers long is a neat, medium size. 

Zhang teamed up with Joseph Wang, a fellow bioengineer in the same department at UCSD. Zhang’s and Wang’s teams filled biodegradable nanoparticles with antibiotics. Then they coated the nanoparticles with cell membranes derived from human immune cells, which made the nanoparticles look more human-like and avoided immune system activation. Finally, using click chemistry, a modular chemical method of attaching molecules to each another, they fused the coated nanoparticles to the outside of algae cells, like buttons on a shirt.

Zhang and Wang tested the microrobot’s ability to deliver the antibiotic-filled nanoparticles and clear infections in mice infected with Pseudomonas aeruginosa, a common cause of pneumonia that frequently develops resistance to antibiotics (3). The teams squirted the microrobots down a feeding tube into infected mouse lungs. The microrobots swam randomly through the lungs and actively delivered antibiotics to the body longer than antibiotics delivered conventionally. 

The random swimming was key. Traditional antibiotics passively float around and unevenly diffuse drugs across tissues. The algae zigged and zagged, dodging immune cells that slowly chased after them. This meant that the drug reached all corners of the lung. The persistent swimming paid off; the microrobots required a 3000-fold lower dose of antibiotics to clear the infection than an intravenous transfusion of the same antibiotics against the same bacteria.

The microrobots cleared the infections within one week, and all mice that received the treatment were still alive 30 days later. Infected mice that received no treatment died within three days. Once the algae cell microrobots delivered their antibiotic payloads, immune cells captured and digested the algae within 72 hours.

“This is a highly interesting project. In the past, bioinspired bots were usually based on synthetic micro/nanorobots or bacteria,” said Wei Gao a medical engineer at California Institute of Technology who wasn’t involved in the research. “Synthetic microrobots face limitations in realizing efficient propulsion in vivo, while bacteria-based bots raise safety concerns for in vivo applications.” 

Nevertheless, the immune system’s response to algae-based microrobots is still not fully understood. Gao suspects that scientists will need to improve the retention time in the body to make microrobots a viable drug delivery system. 

Just a week after publishing their work on clearing lung infections, Zhang and Wang demonstrated another drug delivery system powered by algae to shuttle chemotherapeutics inside a pill into the gastrointestinal tract (4). The next step for the researchers is to figure out how to make their algae drug delivery system work in humans.

“We can click nanoparticles onto algae. But we don’t know how reliable that process is when you [expand] out from this very small scale to larger scale,” said Zhang.

References

1. Zhang, F. et al. Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia. Nat. Mater. (2022). doi:10.1038/s41563-022-01360-9
2. Allahverdiyev, A. M., Kon, K. V., Abamor, E. S., Bagirova, M. & Rafailovich, M. Coping with antibiotic resistance: combining nanoparticles with antibiotics and other antimicrobial agents. Expert Review of Anti-infective Therapy  9, 1035–1052 (2011).
3. Pang, Z., Raudonis, R., Glick, B. R., Lin, T.-J. & Cheng, Z. Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies. Biotechnology Advances  37, 177–192 (2019).
4. Zhang, F. et al. Gastrointestinal tract drug delivery using algae motors embedded in a degradable capsule. Sci Robot  7, eabo4160 (2022).