Study: Ultrasound-activated Nanobubbles Break Down the Structure that Makes Tumors Impenetrable to Treatment

Researchers at Case Western Reserve University have found a way to breach the extracellular matrix (ECM) that, due to excessive accumulation and cross-linking of proteins, particularly collagen, is the most stubborn defense that solid tumors build around themselves.[1]

Virtually impenetrable, the elevated stiffness creates a physical barrier that prevents immune cell infiltration and the effective delivery of various immunotherapeutic agents, such as lipid nanoparticle-based RNA therapeutics.

A new approach that uses ultrasound-activated nanobubbles may increase tumor permeability and immunogenicity. [1]

By injecting nanobubbles filled with inert gas into tumors and ‘jiggling’ them with ultrasound, the team successfully broke down tumor barriers enough for treatment-bearing molecules to enter, according to results from a new study, funded by grants from the Case Comprehensive Cancer Center and the National Institutes of Health (NIH) and published in ACS Nano. [1]

“The physical barrier is limiting delivery of cancer drugs, especially for new immunotherapies,” said Efstathios “Stathis” Karathanasis, Ph.D., vice chair and professor of biomedical engineering, a joint department of the Case School of Engineering and Case Western Reserve School of Medicine.

“We developed a strategy that uses ultrasound-activated nanobubbles, which gently remodels the tumor microenvironment and effectively collapses the tumor walls, opening the door for drugs and immune cells.”

The therapy could potentially be fast-tracked to clinical testing because the nanobubbles are already being commercialized for detecting prostate cancer, and the ultrasound is approved by the U.S. Food and Drug Administration (FDA) and commercially available.

How it works
As tumors grow, they create unusually stiff, dense tissue around them—made mostly from collagen, the protein that forms scar tissue. This barrier prevents modern immune therapies, particularly RNA carried in lipid nanoparticles, from reaching immune cells inside the tumor.

In a breast cancer model, the researchers injected nanobubbles filled with an inert gas, perfluoropropane, into a tumor. Then, using ultrasound, they directed sound waves at the tumor to gently ‘jiggle’ the bubbles, breaking down the tumor’s stiff structure without destroying cells.

The collaboration between Karathanasis’s nanotechnology and immunotherapy lab and the ultrasound and nanomedicine lab of Agata Exner, Ph.D., the Henry Willson Payne Professor of Radiology in the medical school, and director of the CWRU Center for Imaging Research, found that the tumors became softer, more homogeneous, and more penetrable by immune cells and nanoparticles.

“We drop the defenses of the cancer and give a fair chance for our therapies to actually win,” said Exner, also a professor of biomedical engineering.

“We didn’t invent a new drug, but it has the potential to make any existing or emerging therapy work much better,” Exner added.

Activating the body’s own defenses
Even more remarkable is that the treatment activated immune cells already present in tumors without additional therapies.

“They start secreting danger signals and recruiting more immune cells to the site of the tumor,” Karathanasis noted.

“Not only that, the killer T-cells that target that cancer will also seek out other tumors—even ones that weren’t treated,” Karathanasis added.

The nanobubble treatment kept tumors softer for at least five days, whereas untreated tumors grew stiffer and more difficult to treat. When the researchers later injected lipid nanoparticles containing RNA that enhanced the tumor’s T-cell activity, the treatment spread throughout the tumor rather than remaining at the injection site.

Path to clinical trials
“Any tumor that you can biopsy can potentially have nanobubbles introduced,” Exner explained.

“This is especially important for solid tumors that are difficult to treat, where ultrasound is already used, like liver, prostate, and ovarian cancers,” she concluded.

Commercialization
The nanobubbles, developed in Exner’s lab, are being commercialized by Visano Theranostics, a company she co-founded, to detect prostate cancer.

Exner said an Investigational New Drug (IND) application will be submitted to the FDA within the next 18 months, and the therapeutic use could piggyback on that application, potentially enabling clinical trials within two years.

Reference
[1] Bhalotia A, Hutchinson DW, Kosmides T, Nittayacharn P, Mehta M, Iyer A, Cheplyansky A, Takizawa KH, Nidhiry A, Dever AM, Cousens KA, Hwang IM, Ramamurthy G, Exner AA, Karathanasis E. Enhanced Delivery of Lipid Nanoparticle-Based Immunotherapy by Modulating the Tumor Tissue Stiffness Using Ultrasound-Activated Nanobubbles. ACS Nano. 2026 Feb 10;20(5):4592-4606. doi: 10.1021/acsnano.5c21787. Epub 2026 Jan 28. PMID: 41605132; PMCID: PMC12885110.

Featured image licensed under the Unsplash+ License. Used with permission.

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