Revolutionary Microrobots Deliver Drugs with Precision

In a recent study, a team from Caltech used microrobots to shrink bladder tumors in mice—a promising step forward for future medical treatments.

In the future, delivering therapeutic drugs with pinpoint accuracy could be the job of tiny robots—though not the humanoid or animal-like robots often depicted in science fiction. Instead, imagine bubble-like spheres small enough to navigate the human body.

These microrobots need to meet a long list of challenges. They must survive harsh bodily fluids, like stomach acid, be controllable to reach specific targets, release their drug payloads only where needed, and eventually be safely absorbed by the body without causing harm.

The Caltech has achieved just that with its bioresorbable acoustic microrobots (BAM). These tiny robots successfully delivered drugs to shrink bladder tumors in mice, a promising breakthrough for future medical treatments. Their work is detailed in Science Robotics.

We have designed a single platform that can address all of these problems. Rather than putting a drug into the body and letting it diffuse everywhere, now we can guide our microrobots directly to a tumor site and release the drug in a controlled and efficient way. 

Rather than putting a drug into the body and letting it diffuse everywhere, now we can guide our microrobots directly to a tumor site and release the drug in a controlled and efficient way

Wei Gao, Professor and Study Co-Corresponding Author, California Institute of Technology

While the idea of micro- and nanorobots isn’t new, applying them in living systems has proven difficult. Moving tiny objects through complex fluids like blood or urine is incredibly challenging, according to Gao. The robots also need to be biocompatible and leave no toxic residue behind.

The Caltech team’s microrobots are made from a hydrogel called poly(ethylene glycol) diacrylate, which starts as a liquid and solidifies into a polymer network. This material can hold large amounts of fluid, making it biocompatible. Using advanced manufacturing techniques, the researchers created spherical microstructures that can carry therapeutic drugs to precise locations in the body.

While the idea of micro- and nanorobots isn’t new, applying them in living systems has proven difficult. Moving tiny objects through complex fluids like blood or urine is incredibly challenging, according to Gao. The robots also need to be biocompatible and leave no toxic residue behind.

The Caltech team’s microrobots are made from a hydrogel called poly(ethylene glycol) diacrylate, which starts as a liquid and solidifies into a polymer network. This material can hold large amounts of fluid, making it biocompatible. Using advanced manufacturing techniques, the researchers created spherical microstructures that can carry therapeutic drugs to precise locations in the body.

To create these intricate microstructures, Gao collaborated with Julia Greer, a professor at Caltech specializing in nanoscale fabrication. Greer’s team used two-photon polymerization lithography—a technique similar to 3D printing but with much higher precision—to "write" microstructures just 30 microns wide, about the size of a human hair.

This particular shape, this sphere, is very complicated to write. You have to know certain tricks of the trade to keep the spheres from collapsing on themselves. We were able to not only synthesize the resin that contains all the biofunctionalization and all the medically necessary elements, but we were able to write them in a precise spherical shape with the necessary cavity.

Julia R. Greer, Ruben F. and Donna Mettler Professor, California Institute of Technology

The final version of these microrobots integrates magnetic nanoparticles and therapeutic drugs within their outer structure. The magnetic nanoparticles enable researchers to guide the robots to specific locations in the body using an external magnetic field. Once the microrobots reach their target, they stay in place, and the drug gradually diffuses out, ensuring precise delivery.

To prevent the robots from clumping together as they navigate the body, the exterior of the microrobots is designed to be hydrophilic, meaning it attracts water. However, their interior must be hydrophobic (water-repelling) to trap an air bubble, a crucial feature for propulsion and stability, as bubbles are prone to collapsing or dissolving.

To achieve this dual nature, the researchers developed an innovative two-step chemical modification process. First, they made the entire structure hydrophobic by attaching long-chain carbon molecules to the hydrogel. Then, they used oxygen plasma etching to selectively remove these molecules from the exterior, creating a hydrophilic outer surface while maintaining the hydrophobic interior. This clever design ensures the microrobots function effectively in the body’s complex environments.

This was one of the key innovations of this project. This asymmetric surface modification, where the inside is hydrophobic and the outside is hydrophilic, really allows us to use many robots and still trap bubbles for a prolonged period in biofluids, such as urine or serum.

Wei Gao, Professor and Study Co-Corresponding Author, California Institute of Technology

The team demonstrated that their design allows the bubbles inside the microrobots to remain stable for several days, a significant improvement over the few minutes typical without this innovation. These trapped bubbles are essential not only for propelling the robots but also for tracking their movement using real-time imaging.

To enable propulsion, the researchers gave the microrobots two cylinder-like openings—one at the top and one to the side. When exposed to an ultrasound field, the bubbles inside the robots vibrate, creating fluid streams that exit through the openings. This propels the robots forward. The dual-opening design proved highly effective, allowing the microrobots to move faster and navigate various viscous biofluids more efficiently than designs with a single opening.

The trapped bubbles also serve as ultrasound imaging contrast agents, enabling precise, real-time monitoring of the robots as they travel through the body. This capability was developed in collaboration with ultrasound imaging experts, including Mikhail Shapiro, Di Wu, and Qifa Zhou, who brought advanced expertise from Caltech and USC to the project.

In the final stages of development, the team tested the microrobots on mice with bladder tumors. Over a 21-day period, four therapeutic deliveries using the robots significantly reduced tumor size, outperforming traditional drug delivery methods. These results highlight the potential of microrobots as a highly effective tool for targeted drug delivery.

We think this is a very promising platform for drug delivery and precision surgery. Looking to the future, we could evaluate using this robot as a platform to deliver different types of therapeutic payloads or agents for different conditions. And in the long term, we hope to test this in humans.

Wei Gao, Professor and Study Co-Corresponding Author, California Institute of Technology

Video Credit: California Institute of Technology