������Ƶ18

For many undergraduate students, CU Boulder’s��Summer Program for Undergraduate Research (SPUR) is an opportunity to obtain early hands-on experience in a lab setting.

Aiming to increase undergraduate research engagement and interest, the program pairs nearly 125 engineering students from across the college in research labs with faculty members and graduate mentors. For 10 weeks, students foster unique, hands-on research experiences and develop crucial skills that serve them well beyond their undergraduate journey.

But for Joshua Smith, it was more than just exposure and learning—it was the chance to contribute to a real scientific breakthrough.

Smith, an undergraduate student in the��Biomedical Engineering Program (BME), started his SPUR research journey under the supervision of Assistant Professor��Wyatt Shields and graduate mentor Bianca Santana in the��Shields Lab. Their project, like something straight out of a health sci-fi movie, involved studying a method of drug transport to the lungs using tiny microrobots to treat acute respiratory distress syndrome (ARDS).��

“Usually, therapies are based on something called ‘passive delivery,’ which means a drug is injected or inhaled and the patient is left to hope everything works okay from there,” said Smith. “In this method of drug delivery, not much of the treatment actually gets where it needs to go. We’re trying to develop a new method of active transport where we can direct where those drugs go after they enter the body.”

The winding road to treatment

ARDS is a life-threatening lung condition characterized by severe lung inflammation and fluid build-up. It often arises as a complication of other illnesses or injuries and has been seen to develop in a significant percentage of COVID-19 patients—nearly 61 to 81% of those requiring intensive care, according to a study in the National Library of Medicine.

��

BME undergraduate student Joshua Smith working alongside graduate mentor Bianca Santana of the Shields Lab. (Credit: Jesse Morgan Petersen)

Most ARDS treatment options today are ill-equipped to address the underlying cause of the illness. Current therapies merely look to support the patient and improve select symptoms.

That’s why Smith and his lab group began exploring RNA-based gene therapy, a next-generation therapeutic approach that uses molecules from ribonucleic acid to influence genetic expression, modulate biological pathways and treat diseases.

“We are testing circular RNA, which is a different kind of RNA. Its ends are covalently bonded together, meaning it's less susceptible to degrading enzymes and immune responses,” Smith said.��

RNAs face difficulties crossing cellular membranes on their own, so the group is exploring another new solution: pairing them with lipid nanoparticles (LNPs). These tiny, spherical vesicles encapsulate the RNA and increase membrane permeability, allowing them to access the cell.

But that’s not the only obstacle. Drug delivery, especially to the lungs, is extremely difficult. The lungs are protected by a viscous mucosal barrier that acts as a physical shield, trapping and blocking potentially infectious inhaled particles and pathogens.

Smith says that’s where the microrobots come in. By attaching the LNPs to the biodegradable, polymeric microbots, he and his team believe they have the power to overcome the tough layer of mucus and safely deliver drugs to the lungs in a much more targeted manner.

“These little bots—we can control them using acoustic, electric and rotating magnetic fields,” said Smith. “If our project is successful, it can lead to much more of the drug reaching its intended destination, thus making the RNA way more effective and efficient.”

Early exposure to discovery

For Smith, a certain allure behind the project captured his curiosity.

“I was looking through SPUR projects one night and I saw the word ‘robot’ in the chemical engineering section. Honestly, it just sounded like it was interdisciplinary and super cool,” Smith said. “When you get to combine two different fields, that’s the best part about science.”

But it wasn’t just a learning experience. Smith said he was able to observe first-hand, and even play a role in a key discovery.

��

Smith inspecting a piece of lab equipment in the Shields Lab. (Credit: Jesse Morgan Petersen)

“We tested cell viability in circular RNA over the course of a five-day experiment. We were looking to see how much protein the cells produced when exposed to circular RNA as opposed to linear RNA,” said Smith. “We found that circular RNA produced 20 times more protein than linear RNA for a longer period of time. This means the therapies we are working on can be 20 times more effective and last a day longer than other industry standards.”

Smith says these findings have the potential to make a broad impact in the field of gene therapy as a whole, not just ARDS.

“Our project is unique because we’re not just focusing on a specific drug,” Smith said. “We’re focused on drug delivery. Our experiment can easily be applied to other areas, or at least the base concepts of RNA-based gene therapy.”

Going forward, Smith’s experience in the lab has inspired him to potentially pursue medical school after his undergraduate journey. It also illuminated other career fields with ample opportunities to conduct important research.

Regardless of where he ends up, Smith says he’ll bring a strong air of confidence with him.��

“There’s definitely expectations and a steep learning curve when it comes to working in a lab,” said Smith. “But throughout the summer, I feel like I grew to be more of a partner, not just a mentee. I was a big contributor to our project and I’m excited to apply what I learned towards my future.”