USC researcher Longwei Liu uses ultrasound and genetic engineering to develop targeted treatments for blindness and other diseases

USC researcher Longwei Liu, PhD, has made it his mission to develop a therapeutic strategy to narrowly target immunotherapy and gene editing by using focused ultrasound directed inside the body. This technology could have applications for diseases ranging from pediatric blindness to cancer.

His goal is to address a hard-to-shake dynamic that shows up too often in medical care. Treatments effective against serious diseases such as cancer can be toxic for patients because they also affect healthy tissue. This is a problem seen even in many targeted therapies.

Liu’s solution combines ultrasound with genetic engineering to act as an “on-off switch,” noninvasively activating treatment only when and where it’s needed.

“Turning on only in the diseased region would maximize efficacy,” said Liu, an assistant professor of ophthalmology and biomedical engineering at the Keck School of Medicine of USC and USC Viterbi School of Engineering, and a Baxter Foundation faculty fellow. “And ensuring other organs don’t receive any stimulation would make the therapy safer.”

Hot on the trail of biomedical advances

To develop this new therapeutic strategy, Liu and his team piggybacked on a survival mechanism that makes our bodies resilient to hot temperatures. Environmental stress, such as heat shock, kicks off a cascade of biochemical signals that ultimately stabilize fundamental cellular processes.

In this cascade, the researchers identified a key signaling protein and developed an engineered version of it to activate treatment. From there, energy from focused ultrasound generates heat that can work as an on switch for this engineered protein.

“Evolution gave human beings a protection mechanism when temperatures get high,” Liu said. “My research repurposes that natural protection to make the cells respond to the heat generated by sound.”

A pilot application for this technology is gene therapy for an inherited retinal disorder known as Leber congenital amaurosis (LCA). This rare disease is a leading cause of blindness in children. Liu seeks to improve outcomes by triggering gene therapy only within the eye.

“We are looking for a fundamental way to directly change the patient’s genetic code, fix the mutated gene using CRISPR technology,” he said.

His aspirations stretch beyond any one condition, though. LCA is one of 6,000 genetic disorders in humans, and most of them lack an effective treatment.

“This is a platform technology,” Liu said. “We don’t want to limit ourselves to one specific disease.”

How imaging innovations inform bold treatment strategies

Liu earned his PhD from Tsinghua University in China in 2019 before completing postdoctoral training in real-time cellular imaging and molecular engineering at the University of California San Diego in the lab of Peter Yingxiao Wang, PhD, who now holds USC’s Dwight C. and Hildagarde E. Baum Chair in Biomedical Engineering. In 2025, Liu launched his own independent lab at the Keck School of Medicine.

In previous work, Liu has demonstrated that local activation with ultrasound can enhance an immunotherapy for cancer called CAR T cell therapy. CAR T therapy, currently approved for blood cancers, involves engineering a patient’s own immune cells to express receptors that specifically target cancer.

The researchers’ “Echoback CAR T cell” technology is designed for solid cancers by using high-frequency soundwaves to drive the growth of extra targeting receptors on CAR T cells when they’re near the disease site. This concentrates therapeutic activity within the tumor while reducing toxicity elsewhere.

Lab experiments indicated that the approach extended the amount of time therapeutic cells stay active against prostate and brain tumors.

Those results were only possible due to the groundwork laid by the researchers’ work developing imaging innovations, including biosensors that light up proteins to trace cellular functions as they occur. It gave Liu unique insight into the biochemistry that controls T cells.

“People often ask how we fished out those elements in our research,” he said. “I knew which signaling pathways were being activated because I spent several years studying T cell behavior using our fluorescent imaging.”

Balancing curiosity and practicality

The team also had to surmount another hurdle along the path to ultrasound-triggered treatments: Although the natural protective mechanism is associated with heat shock, it’s also spurred by other stressors.

Therefore, they needed to identify a signaling element that responds only to heat.

Liu approached Wang with an unconventional idea. In addition to the typical approach of screening a library of naturally occurring signaling proteins related to the body’s protection against heat stroke, why not also screen engineered ones created by their team?

It turned out that one of their engineered circuits had superior heat-specific behavior.

Liu is grateful for the mentorship he’s received from Wang and, before that, his graduate studies adviser at Tsinghua University in China, Yanan Du, PhD.

“They encouraged me to ask bold questions and gave me advice on how to make the engineering approach practical,” he said. “That’s the philosophy I bring to my lab. As mentors, the way we protect trainees’ curiosity is by helping them step-by-step to make sure what they’re doing is realistic.”

Vital links

Trojan connections were a major factor in Liu’s choice to launch his independent lab at USC.

He also values the synergy between USC’s schools of medicine and engineering, exemplified by the recent move to make the Alfred E. Mann Department of Biomedical Engineering a joint department of the Keck School of Medicine and USC Viterbi.

“I was really inspired by the university’s vision in bringing the schools together,” Liu said.

Being embedded in the medical school allows him opportunities to work with clinicians whose perspectives help shape his studies. For example, he’s working to translate one of his biosensors into humans for tracking drug response, at the behest of physician colleagues.

“I have seen the power of engineering in medicine,” Liu said. “The concept is putting myself into an environment where I have a chance to talk to medical doctors. They’re the first line, seeing the patients and delivering therapies, so they know exactly what the unmet needs are.”