By Nana O 
Researchers at Washington University School of Medicine in St. Louis, collaborating with scientists at Northwestern University, have unveiled a groundbreaking noninvasive strategy to combat glioblastoma, one of the most aggressive and deadly forms of brain cancer. This innovative method utilizes precisely engineered nanostructures, delivered via simple nasal drops, to ferry potent cancer-fighting compounds directly into the brain and, crucially, to stimulate the body’s own immune system to attack the tumor. In preclinical studies involving mice, this approach demonstrated significant success in treating glioblastoma, offering a promising alternative to highly invasive treatments currently under development. The findings, published this month in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), represent a significant leap forward in the quest for effective glioblastoma therapies.
The Elusive Target: Glioblastoma’s Resistance to Treatment
Glioblastoma multiforme (GBM) is a formidable adversary in the field of oncology. Arising from astrocytes, a type of glial cell in the brain, it stands as the most prevalent and aggressive malignant primary brain tumor in adults. In the United States, approximately three out of every 100,000 individuals are diagnosed with this devastating disease annually. Its rapid progression and notoriously poor prognosis, with a median survival rate often measured in months, underscore the urgent need for more effective therapeutic interventions.
A primary hurdle in treating glioblastoma is the inherent difficulty in delivering therapeutic agents to the brain. The blood-brain barrier (BBB), a highly selective physiological barrier that protects the central nervous system from circulating toxins and pathogens, also significantly restricts the passage of most drugs. This means that conventional systemic drug administration often fails to achieve therapeutic concentrations within the brain tumor site.
"Our overarching goal was to fundamentally alter this therapeutic landscape," stated Dr. Alexander H. Stegh, a professor and vice chair of research in the Taylor Family Department of Neurosurgery at WashU Medicine and a co-corresponding author of the study. Dr. Stegh, who also directs research for The Brain Tumor Center at Siteman Cancer Center, a joint venture of Barnes-Jewish Hospital and WashU Medicine, elaborated, "We sought to develop a noninvasive treatment paradigm that could effectively leverage the brain’s intrinsic immune mechanisms to combat glioblastoma. This research validates the potential of meticulously designed nanostructures, specifically spherical nucleic acids, to safely and potently activate crucial immune pathways within the brain. This opens up entirely new avenues for cancer immunotherapy, particularly for tumors that have historically been difficult to access."
Harnessing the Immune System: Reactivating the STING Pathway
A key characteristic that contributes to glioblastoma’s resistance to immunotherapy is its classification as a "cold tumor." Unlike "hot tumors," which are infiltrated by immune cells and exhibit a robust immune response, glioblastomas are often adept at evading immune surveillance. This immune evasion is partly due to a lack of intrinsic inflammatory signals that would typically alert the immune system to the presence of cancer cells.
Scientists have long been investigating ways to overcome this immune deficiency, with particular interest in the STING (stimulator of interferon genes) pathway. The STING pathway acts as a critical innate immune sensor. When cellular or extracellular DNA is detected in the cytoplasm, it can trigger the STING pathway, initiating a cascade of events that leads to the production of interferons and other immune signaling molecules. This, in turn, primes the immune system to recognize and attack aberrant cells, including cancer.
Previous research had demonstrated that activating the STING pathway could indeed prime the immune system to target glioblastoma. However, a significant limitation of existing STING-activating drugs is their inherent instability. They are prone to rapid degradation in the body and, to achieve any therapeutic effect, must be directly injected into the tumor. Given that multiple doses are typically required for efficacy, this necessitates repeated, highly invasive surgical procedures. For patients already grappling with a devastating diagnosis and the rigors of cancer treatment, such invasive interventions pose a considerable burden.
"We were deeply motivated to alleviate the burden on patients who are already facing immense health challenges," explained Dr. Akanksha Mahajan, a postdoctoral research associate in Dr. Stegh’s laboratory and the first author of the study. "The idea was to explore whether the spherical nucleic acid platform could serve as a vehicle for delivering these potent immune-activating drugs in a manner that completely bypasses the need for invasive procedures."
Engineering Nanostructures for Nose-to-Brain Delivery
To translate this vision into reality, Dr. Stegh’s team joined forces with Dr. Chad A. Mirkin, the director of the International Institute for Nanotechnology and the Rathmann Professor of Chemistry at Northwestern University. Dr. Mirkin is a pioneer in the field of nanotechnology and the development of spherical nucleic acids (SNAs). SNAs are nanoscale particles characterized by a dense arrangement of DNA or RNA molecules densely packed around a core. This unique architecture has been shown to confer enhanced cellular uptake and biological activity compared to conventional nucleic acid delivery systems.
The collaborative effort focused on designing a specialized iteration of SNAs. These engineered nanostructures featured a gold nanoparticle core, which provides a stable scaffold, surrounded by short DNA fragments specifically designed to activate the STING pathway within targeted immune cells. The critical innovation lay in the chosen route of administration: the nasal passages.
Intranasal delivery has been explored as a potential method for targeting the brain, as the olfactory and trigeminal nerve pathways offer a direct route from the nasal cavity to the central nervous system, circumventing the BBB to some extent. However, until this research, no nanoscale therapeutic had successfully demonstrated the ability to elicit a robust immune response against brain tumors via this noninvasive route.
"This study marks a significant milestone, as it is the first to demonstrate that delivering nanoscale therapeutics through the nose can effectively enhance immune cell activation within glioblastoma tumors," Dr. Mahajan emphasized. This finding is particularly noteworthy as it validates the potential of a truly noninvasive approach for brain cancer immunotherapy.
Tracing the Nanodrops: From Nasal Passage to Tumor Site
A crucial aspect of this research was to meticulously track the nanostructures to confirm both their targeted delivery to the brain and their ability to elicit the desired immune response. To achieve this, the researchers incorporated a molecular tag into the SNAs that emits a fluorescent signal detectable under near-infrared light.
Following the administration of these "nanodrops" to mice engineered to carry glioblastoma tumors, the researchers observed the particles traversing along the olfactory nerve pathway, the primary neural connection linking the nasal region to the brain. Crucially, the nanomedicine’s activity was found to be concentrated within specific immune cells located within the tumor microenvironment. Some immune activation was also noted in nearby lymph nodes, which play a vital role in initiating and regulating immune responses. Importantly, the systemic distribution of the therapy throughout the body was minimal, thereby reducing the likelihood of off-target effects and systemic toxicity.
Further investigations confirmed that the STING pathway had been successfully activated in immune cells both within and surrounding the tumor. This activation empowered these immune cells to mount a more potent and effective attack against the cancerous cells, a critical step in controlling tumor growth.
Synergistic Strategies: Enhancing Treatment Efficacy and Preventing Recurrence
The research team further explored the potential of combining this novel nanotherapy with other immunomodulatory agents. When the STING-activating nanodrops were administered in conjunction with drugs designed to activate T lymphocytes – another crucial component of the immune system’s anti-cancer arsenal – the results were remarkably encouraging. This two-pronged approach led to the complete eradication of tumors in the treated mice.
Moreover, the combination therapy induced a durable anti-tumor immune memory. This means that the mice that had their tumors eliminated were subsequently resistant to re-challenge with glioblastoma cells, indicating a long-lasting protective immune response that prevented cancer recurrence. These outcomes significantly surpassed the efficacy observed with current STING-targeting therapies, highlighting the superior potential of this nanostructure-based approach.
Despite these promising results, Dr. Stegh cautioned that activating the STING pathway alone may not be sufficient to achieve a complete cure for glioblastoma. He explained that glioblastoma employs a complex array of mechanisms to suppress or shut down anti-tumor immune responses. To address this, his group is actively working on incorporating additional immune-activating functionalities directly into the nanostructures. The long-term vision is to develop a single therapeutic agent capable of simultaneously targeting multiple immune pathways, thereby enhancing its overall efficacy against this notoriously resistant cancer.
"This innovative approach holds substantial promise for developing safer and more effective treatments for glioblastoma and potentially other cancers that are resistant to current immunotherapies," Dr. Stegh concluded. "This represents a critical and exciting step forward towards the eventual clinical application of this technology."
Funding and Disclosure: A Collaborative Effort
This groundbreaking research was made possible through significant financial support from various national and institutional bodies. Key funding was provided by the National Cancer Institute of the NIH under grant numbers P50CA221747 and R01CA275430, and by the NIH through grants R01CA120813, R01NS120547, and R01CA272639. Additional support came from the Melanoma Research Foundation, the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University, and grants from Cellularity, Alnylam, and AbbVie. Imaging services at the Siteman Cancer Center Small Animal Cancer Imaging facility were supported by NIH instrumentation grants S10OD027042 and S10OD025264, as well as the National Cancer Institute Cancer Center grant P30CA091842. PET and MRI imaging were facilitated by the Robert H. Lurie Comprehensive Cancer Center Grant P30CA060553.
It is important to note that the content of this publication is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health.
The study also involves potential competing interests. Dr. Alexander Stegh is a shareholder of Exicure Inc., a company that develops SNA therapeutic platforms. Dr. Chad Mirkin is a shareholder in Flashpoint, a company focused on developing SNA-based therapeutics. Both Dr. Stegh and Dr. Mirkin are co-inventors on patent US20150031745A1, which outlines the use of SNA nanoconjugates for crossing the blood-brain barrier. These disclosures are standard practice in scientific research and are intended to ensure transparency regarding potential influences on the research findings.