Researchers with the University of Cincinnati and Johns Hopkins Medicine developed a potential treatment for brain cancer that uses nanofibers embedded with a combination of drugs that work in concert to target tumors.

The drugs proved more effective in combination than when administered alone and can provide both immediate and long-lasting doses to kill cancer cells.

Lead author Daewoo Han, an assistant professor in UC’s College of Engineering and Applied Science, and UC Distinguished Research Professor Andrew Steckl incorporated the drugs into electrospun fiber membranes, creating a nanofiber drug delivery system. Steckl’s NanoLab at the University of Cincinnati is a leading developer of this technology that uses an electric field to create a multilayered fiber mesh for drug delivery, among other uses.

“This combination is pretty powerful,” Steckl said.

Glioblastoma is the most common and aggressive form of brain cancer in adults. Researchers at UC and Johns Hopkins found that the three federally approved drugs used to treat glioblastoma (temozolomide, acriflavine and PT2385) work better in combination than they would alone, a pharmaceutical phenomenon called synergism.

“When you add them together, three things can happen,” Steckl said. “The combination is negative; the effect is additive, like one plus one equals two; or it’s synergistic, which is like one plus one equals three.”

The study was published in the journal ACS Biomaterials Science & Engineering. The research was supported with a grant from the National Institutes of Health.

Steckl said glioblastoma is extremely difficult to treat because its heterogeneous cells allow for mutations that help the cancer evade treatment.

“It’s tough to control,” Steckl said. “It comes in through the window and when you close the window, it comes through the door. And when you close that, it comes through the chimney.”

Glioblastoma also has high recurrence. And the blood-brain barrier limits the effectiveness of other traditional chemotherapies.

“Our NanoMesh system was designed to solve these issues by enabling localized long-term delivery of multiple synergistic drugs directly at the tumor site after surgery,” UC’s Han said.

UC researchers worked with a team at Johns Hopkins Medicine, including Betty Tyler, a professor of neurosurgery, and postdoctoral researcher Hasan Slika. Tyler said researchers are looking to attack the disease with combinations of therapies.

“Unfortunately, cancers know how to pivot to evade therapeutic treatment,” she said. “So we’re approaching treatment multidimensionally.”

Tyler has helped develop other cutting-edge therapies now commonly used to treat cancer.

“Current therapies have increased patient survival and given them more birthdays,” she said. “But we’re still working on improving options.”

In animal trials, all untreated mice with glioblastoma died within 19 days. But a majority of mice treated with the three-layer nanofiber mesh survived twice as long. And 40% survived past the 120-day conclusion of the experiment in a plateau that stretched for more than 80 days.

Han said using electrospun fiber mesh, doctors can precisely control the dosage and release and the implant geometry, which contribute to its effectiveness. And just as the blood-brain barrier protects the brain from toxins, the barrier also protects the body from the toxic side effects of the medicine applied to the brain, Han said.

UC researchers are now working on optimizing the long-term release of medicines using advanced nanofiber structures. And the delivery system has broad potential in applications for other difficult-to-treat diseases, Han said.

“What’s next will be very exciting,” Han said. “Our ultimate goal is moving forward to a clinically translatable system that improves both survival and quality of life for patients with difficult-to-treat cancers, including glioblastoma.”

Journal

ACS Biomaterials Science & Engineering

Funder

NIH/National Institutes of Health

DOI

10.1021/acsbiomaterials.5c01482

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Glioblastoma’s notorious resistance to current treatments stems from its infiltrative nature, aggressive growth patterns, and the brain’s complex immune microenvironment. Surgical removal remains the primary mode of intervention; however, microscopic residual cancer cells invariably persist, leading to nearly universal relapse. The new study, recently reported in Nature Communications, pioneers an intervention that is administered immediately following surgical resection, leveraging the window of opportunity to prime the immune system against remaining tumor cells.

Central to this promising therapy is the use of a toll-like receptor (TLR) 7/8 agonist embedded within a biodegradable scaffold implanted in the resection cavity. TLR7 and TLR8 are pattern recognition receptors known to activate innate immune mechanisms that reignite anti-tumor immunity. By localizing the delivery of this immune stimulant, the scaffold acts as a microenvironmental modulator, recruiting and activating immune cells in proximity to residual cancer cells, thus transforming a typically immunosuppressive niche into an immune hotbed.

The biodegradable scaffold itself is engineered with meticulous precision, crafted from materials that degrade safely and predictably in the brain over a set timeframe. This controlled degradation is critical, ensuring a sustained release of the TLR7/8 agonist that prolongs immune activation without triggering systemic toxicity. The localized delivery method circumvents the challenges of systemic immunotherapy, including off-target side effects and poor blood-brain barrier penetration, which have limited previous attempts at immunomodulation in glioblastoma.

Experimental validation of this scaffold-based delivery system was conducted in murine models simulating post-surgical glioblastoma treatment. The results were striking: mice that received the TLR7/8 agonist-laden scaffold demonstrated complete tumor clearance in a significantly higher proportion compared to controls. More impressively, these animals exhibited robust immunological memory, enabling resistance to subsequent tumor challenges, a key indicator of long-lasting protective immunity—a milestone rarely achieved in glioblastoma models.

Delving deeper into the immunological landscape, researchers observed a marked increase in infiltrating cytotoxic T lymphocytes and activation markers denoting effective anti-tumor responses. The immune milieu within the treated cavities shifted from one dominated by regulatory, suppressive elements to a pro-inflammatory, tumoricidal environment. This immunodynamic shift is paramount for overcoming glioblastoma’s notorious immunosuppressive tactics, which have thereby far thwarted successful immunotherapy.

The implications of this research extend beyond merely improving local tumor control; it hints at a paradigm shift in how glioblastoma may be managed. Traditional therapies often rely on maximal tumor resection followed by chemotherapy and radiation, which incur significant neurotoxicity and provide marginal survival benefits. This new scaffold-based immunotherapy potentially reduces the reliance on systemic agents by harnessing the patient’s own immune system to recognize and eradicate residual disease with precision and durability.

Moreover, the modularity of the scaffold platform opens avenues for combinatorial treatments. The biodegradation rate, drug payload, and adjuvant combinations can be tailored to individual tumor biology or integrated with emerging checkpoint blockade therapies, thus amplifying therapeutic benefit through multi-modal immunotherapy regimens.

The study also paves the way for reconsidering the timing of immune interventions in brain cancer treatment. By situating immunotherapy within the immediate post-resection interval, the scaffold exploits a critical therapeutic window wherein the immune system may be most amenable to reprogramming, and residual cancer cells are vulnerable yet vulnerable enough to be targeted effectively.

Of paramount importance is the demonstrated safety profile in animal models, showing no adverse neurological or systemic effects attributable to the scaffold or the TLR agonist delivery. This favorable toxicity profile is crucial for potential clinical translation, particularly given the sensitive nature of brain tissue and the severe consequences of neuroinflammation or immune-related adverse events.

The scaffold’s capability to invoke systemic anti-tumor immunity following local application could also revolutionize approaches to metastatic brain cancers and possibly other solid tumors where surgical resection is standard but residual microscopic disease hinders curative outcomes. Immune memory formation observed in the study suggests potential for durable remission, a holy grail in oncology.

Despite these optimistic findings, challenges remain before clinical application. Scaling up production of such scaffolds with consistent quality and ensuring regulatory compliance will require dedicated efforts. Furthermore, the heterogeneous and immunosuppressive microenvironments of human glioblastomas may introduce variability in response, underscoring the need for biomarker-driven patient selection and personalized approaches.

Future research directions illuminated by this study include optimization of the scaffold composition, refinement of TLR7/8 agonist dosing, and combination with other immunomodulatory agents such as checkpoint inhibitors or CAR T-cell therapies. Additionally, humanized models and early-phase clinical trials will be essential to validate efficacy and safety in patients.

In sum, this innovative scaffold-mediated delivery of TLR7/8 agonists offers a beacon of hope in the relentless battle against glioblastoma. Through harnessing innate and adaptive immunity in a localized, controlled manner, this technology transcends prior limitations, charting a promising path toward improved survival and quality of life for patients afflicted with one of the most formidable cancers known.

The marriage of biomaterials science with immunotherapy exemplified in this work not only advances glioblastoma treatment but also sets a precedent for tackling other cancers entrenched in immune-privileged or resistant environments. As the field moves forward, this approach may well signal the dawn of a new era where surgical oncology and immune engineering coalesce to achieve long-sought cures.

With glioblastoma posing immense clinical and scientific challenges, the arrival of such targeted immunotherapeutics invigorates the field and kindles anticipation for transformative outcomes. If replicated and extended in humans, patients may soon benefit from therapies that do not merely extend life but actively engage and empower their own immune systems to eradicate cancer at its roots.

Subject of Research: Immunotherapy for Glioblastoma Using Biodegradable Scaffolds Delivering TLR7/8 Agonists

Article Title: Post-resection delivery of a TLR7/8 agonist from a biodegradable scaffold achieves immune-mediated glioblastoma clearance and protection against tumor challenge in mice.

Article References:
Graham-Gurysh, E.G., Woodring, R.N., Simpson, S.R. et al. Post-resection delivery of a TLR7/8 agonist from a biodegradable scaffold achieves immune-mediated glioblastoma clearance and protection against tumor challenge in mice. Nat Commun 16, 8603 (2025). https://doi.org/10.1038/s41467-025-63692-9

Image Credits: AI Generated