The first fully biodegradable and biocompatible piezoelectric chitosan nanoparticle uses ultrasound to trigger localized stress signals in glioblastoma cells, reducing proliferation and promoting apoptosis.
(Nanowerk Spotlight) Glioblastoma is one of the most difficult cancers to treat. It infiltrates brain tissue, undermines surgical boundaries, and frequently returns even after aggressive therapy. Standard approaches rely on removing the tumor as safely as possible, applying radiation, and using chemotherapy. Yet many glioblastoma cells survive and reseed the tumor. Even electrical stimulation, an approved treatment designed to interfere with cancer cell growth, affects both malignant and healthy cells because electric fields spread through surrounding tissue.
The central limitation is precision. A therapy that can trigger responses inside the tumor itself, without disturbing the rest of the brain, remains elusive.
Piezoelectric materials offer an unusual form of control. These materials produce tiny electrical charges when pressed or vibrated. Ultrasound can reach deep into the body and provide that mechanical push. If nanoscale piezoelectric particles sit inside a tumor, ultrasound can activate them remotely and locally, generating biological effects at the scale of individual cells.
Numerous groups have attempted this strategy with inorganic nanoparticles such as barium titanate or zinc oxide. These materials produce electrical signals and can damage cancer cells, but they do not break down in the body. Organic polymers like poly(vinylidene fluoride-trifluoroethylene) are more compatible with tissue but still do not biodegrade. Both approaches rely on particles that persist indefinitely.
A study published in Small Science (“Ultrasound-Activated Biodegradable Piezoelectric Chitosan Nanoparticles for Glioblastoma Treatment”) presents a different avenue. A team of researchers led by Dr. Gianni Ciofani at the Istituto Italiano di Tecnologia (IIT), developed nanoparticles made entirely from chitosan, a polysaccharide derived from crustacean shells that is already used in biomedical products.
“In our recent work we describe the first totally biodegradable and biocompatible piezoelectric nanoparticle, based on chitosan, here exploited for anticancer therapy,” Ciofani tells Nanowerk. “Unlike previously used materials, these particles require no additional coatings, metals, or drugs. Their function comes from their structure and their response to ultrasound.”
Confocal images show a clear drop in the proliferation marker Ki-67 when glioblastoma cells receive ultrasound plus piezoelectric chitosan nanoparticles, compared with untreated cells, nanoparticles alone, or ultrasound alone. In the same condition, the stress marker p53 increases, indicating that the combined treatment pushes cancer cells away from growth and toward cell-damage responses. (click on image to enlarge)
The nanoparticles are created through a water-in-oil method. Chitosan is dissolved in acidic water and mixed into an oil phase to form droplets. Potassium hydroxide is added at this stage, and that alkaline treatment reorganizes the polymer chains into stable spherical particles. When the same material is produced without potassium hydroxide, the resulting nanoparticles show no measurable piezoelectric behavior. With it, the particles produce a detectable electrical response under stimulation. The performance rivals some inorganic materials and exceeds commonly used piezoelectric polymers.
The team’s measurements show that the chitosan nanoparticles deform electrically in response to applied energy, confirming that the piezoelectric response is not an artifact of additives or coatings. Because chitosan is already used in medical devices and is biodegradable, its properties align more naturally with clinical requirements.
They then asked whether the particles degrade in environments that resemble the body. They found that in conditions similar to healthy tissue, the nanoparticles gradually lost size and mass over several days. In mildly acidic conditions with oxidative stress—features associated with tumor environments—they degraded more quickly. This tendency matches a desirable clinical profile. A particle that disappears faster in cancer tissue than in normal tissue would be less likely to accumulate in the brain over time.
The next question was whether glioblastoma cells would take up the particles at all. The researchers exposed patient-derived cancer cells to fluorescently labeled nanoparticles. Within twenty-four hours, most cells had internalized them, and many particles settled into acidic compartments used for recycling cellular material. After 72 hours, the majority of cancer cells still contained nanoparticles.
“The effects became clear when we applied ultrasound,” Ciofani explains. “Glioblastoma cells exposed to ultrasound alone remained stable. Cells exposed only to nanoparticles also showed no meaningful change. When we combined the two, intracellular calcium began to rise gradually. Cells interpret sustained calcium elevation as a form of stress. It can interrupt their growth cycle or activate pathways that lead to programmed cell death.”
At the same time, a larger share of cells produced reactive oxygen species, unstable molecules that damage cellular machinery when present in excess. Cancer cells are already near their stress limits, which makes them vulnerable to additional oxidative pressure.
After three days of repeated stimulation, the biological changes deepened. Levels of Ki-67, a protein associated with cell proliferation, were high in untreated cultures, in cultures exposed only to ultrasound, and in cultures exposed only to nanoparticles. Under combined treatment, Ki-67 dropped sharply. The cells showed signs of leaving the growth cycle. Another protein, p53, which is associated with DNA damage and apoptosis, rose significantly. More cells entered early programmed cell death, while fewer remained viable. None of these effects were produced by nanoparticles alone or ultrasound alone.
To test whether this behavior extends beyond flat cultures, the team implanted glioblastoma spheroids into the chorioallantoic membrane of quail embryos. This model includes blood vessels and a physical environment that more closely resembles living tissue. After treatment with nanoparticles and ultrasound, the spheroids showed a dramatic loss of Ki-67, while tumors exposed to only one component retained normal levels of proliferation. Tissue sections revealed structural disruption in the treated tumors.
“The combination of piezoelectric responsiveness, biodegradability, and preclinical feasibility highlights the potential of chitosan nanoparticles as a safe, noninvasive therapeutic platform for next-generation cancer treatments,” Ciofani concludes. “Our approach avoids drugs, metals, and synthetic polymers while relying on a single biological material. It activates only when ultrasound is applied, confining its effects to the cells that contain the particles.”
This work does not claim to provide a completed therapy. It presents a material that enters tumor cells, responds to remote stimulation, disrupts growth signals, and breaks down naturally. For a cancer that evades chemical therapies and damages surrounding tissue when approached with surgery, the study points to a different way of thinking about treatment. It uses physics rather than pharmaceuticals to push cancer cells toward their limits while leaving surrounding tissue untouched.
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