By Nana O 
Researchers at Washington University School of Medicine in St. Louis, in collaboration with scientists at Northwestern University, have unveiled a groundbreaking, noninvasive strategy to combat glioblastoma, one of the most aggressive and deadliest forms of brain cancer. This innovative method utilizes precisely engineered nanostructures, delivered via simple nasal drops, to carry potent cancer-fighting compounds directly into the brain. In preclinical studies conducted on mice, this approach demonstrated remarkable success in treating glioblastoma by reactivating and stimulating the brain’s own immune system, a significant advancement that bypasses the invasiveness of current experimental treatments. The findings, published this month in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), represent a pivotal step toward developing safer and more effective therapies for this devastating disease.
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 that supports and protects neurons, it is the most prevalent and aggressive malignant primary brain tumor in adults. In the United States, the incidence is approximately three in every 100,000 individuals annually. The disease is characterized by its rapid growth and infiltrative nature, making complete surgical resection exceedingly difficult. Consequently, the prognosis for glioblastoma patients remains grim, with a median survival rate often measured in months, even with aggressive multimodal treatment regimens.
A primary hurdle in treating glioblastoma effectively 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 severely restricts the passage of most drugs. Conventional systemic administration of chemotherapies often results in insufficient concentrations reaching the tumor site, while localized delivery methods, such as direct tumor injection or intrathecal administration, are inherently invasive and carry significant risks.
"Our objective was to fundamentally alter this therapeutic landscape by devising a noninvasive treatment capable of marshaling the brain’s immune defenses against glioblastoma," stated Alexander H. Stegh, PhD, a professor and vice chair of research in the WashU Medicine Taylor Family Department of Neurosurgery and a co-corresponding author of the study. Dr. Stegh, who also holds a leadership role as research director of The Brain Tumor Center at Siteman Cancer Center, a joint venture of Barnes-Jewish Hospital and WashU Medicine, elaborated on the significance of their work. "Through this research, we have demonstrated that meticulously designed nanostructures, specifically spherical nucleic acids (SNAs), possess the capacity to safely and efficaciously engage potent immune pathways within the brain. This breakthrough redefines the potential for cancer immunotherapy in tumors that are typically challenging to access."
A Novel Approach: Stimulating the Immune System via the STING Pathway
Glioblastoma has long been characterized as an immunologically "cold tumor." This classification stems from its ability to evade detection and attack by the immune system. Unlike "hot tumors," which exhibit a robust infiltration of immune cells and are generally more amenable to immunotherapy, glioblastomas actively suppress anti-tumor immune responses. Scientists have been intensely exploring strategies to overcome this immune evasion, with particular interest focused on pathways that can initiate a potent immune cascade.
One such pathway is STING (stimulator of interferon genes). The STING pathway is a critical component of the innate immune system. It is activated when cells detect the presence of foreign DNA, such as that from invading microbes or damaged host cells. Upon activation, STING triggers a signaling cascade that leads to the production of type I interferons and other inflammatory cytokines, effectively alerting and mobilizing the immune system to combat the perceived threat.
Previous research had indicated that drugs capable of activating the STING pathway could prime the immune system to recognize and attack glioblastoma cells. However, these STING agonists faced significant limitations: they were rapidly degraded in the body, necessitating direct injection into the tumor to achieve therapeutic concentrations. The requirement for multiple, invasive procedures to administer these drugs posed a substantial burden on patients already suffering from a life-threatening illness.
"We were deeply motivated to alleviate the burden of invasive procedures for patients who are already critically ill. Our hypothesis was that we could leverage the unique properties of spherical nucleic acid platforms to deliver these STING-activating drugs in a completely noninvasive manner," explained Akanksha Mahajan, PhD, a postdoctoral research associate in Dr. Stegh’s lab and the first author of the study. This conceptual leap aimed to marry the therapeutic potential of STING activation with the convenience and safety of a noninvasive delivery route.
Engineering Nanostructures for Nose-to-Brain Delivery
To translate this vision into reality, Dr. Stegh’s team forged a crucial partnership with Chad A. Mirkin, PhD, a renowned figure in nanotechnology and director of the International Institute for Nanotechnology and the Rathmann Professor of Chemistry at Northwestern University. Dr. Mirkin is a pioneer in the development of spherical nucleic acids (SNAs). SNAs are nanoscale particles characterized by a dense arrangement of DNA or RNA oligonucleotides on their surface, often anchored to a core material. Their unique structure has demonstrated superior cellular uptake and therapeutic efficacy compared to conventional nucleic acid delivery systems.
The collaborative effort led to the design of a specialized variant of SNAs. These nanostructures featured a gold nanoparticle core, which provided structural integrity and facilitated imaging, surrounded by short DNA fragments engineered to specifically activate the STING pathway within targeted immune cells. The critical innovation lay in the chosen delivery route: the nasal passages.
Intranasal administration has emerged as a promising avenue for delivering therapeutic agents directly to the brain. This route exploits the anatomical proximity of the nasal cavity to the central nervous system, offering a potential bypass of the BBB. However, despite previous explorations, no nanoscale therapeutic had previously demonstrated the capability to effectively activate immune responses against brain tumors via this pathway.
"This marks a significant first," Mahajan emphasized. "It is the inaugural demonstration that we can achieve enhanced immune cell activation within glioblastoma tumors by delivering nanoscale therapeutics from the nose directly to the brain."
Visualizing the Journey: Nanodrops Traverse to the Brain
To rigorously validate their approach, the researchers meticulously tracked the journey and function of these novel nanodrops. They incorporated a molecular tag into the spherical nucleic acids that emitted a fluorescent signal under near-infrared light, allowing for real-time visualization. Following the administration of the nanodrops to mice bearing glioblastoma tumors, the research team observed the particles migrating along the olfactory nerve pathway, a major neural tract connecting the facial region to the brain.
Upon reaching their destination, the immune response triggered by the nanomedicine was found to be highly localized. The activation was concentrated within specific immune cells residing within the tumor microenvironment. Trace amounts of activity were also detected in nearby lymph nodes, suggesting an initial priming of the systemic immune system. Crucially, the therapy did not exhibit widespread distribution throughout the body, a key factor in minimizing the potential for off-target effects and systemic toxicity.
Further microscopic and molecular analyses confirmed that immune cells in and around the tumor had successfully activated the STING pathway. This cellular activation equipped these immune cells with enhanced capabilities to identify and mount a more robust attack against the cancerous glioblastoma cells.
Synergistic Therapies: Eradicating Tumors and Preventing Relapse
The ultimate goal of cancer treatment is not only to eliminate existing tumors but also to prevent their recurrence. The researchers investigated the potential of their nanotherapy in combination with other immune-modulating agents. When the intranasal nanotherapy was paired with drugs designed to activate T lymphocytes – another critical class of immune cells involved in tumor surveillance and destruction – the results were profoundly encouraging.
This two-pronged therapeutic strategy led to the complete eradication of glioblastoma tumors in the treated mice. More remarkably, the treatment induced a long-lasting immune memory, rendering the mice resistant to subsequent glioblastoma re-challenge. These outcomes represented a substantial improvement over the efficacy observed with current STING-targeting therapies, highlighting the synergistic power of combining the noninvasive nanotherapy with T-cell activation.
Dr. Stegh cautioned that activating the STING pathway alone might not be sufficient to achieve a cure for glioblastoma. He acknowledged that glioblastoma employs a sophisticated arsenal of mechanisms to suppress and dismantle anti-tumor immune responses. His research group is actively exploring strategies to engineer their nanostructures with additional immune-activating functionalities. The aim is to create a single therapeutic agent capable of simultaneously targeting multiple immunosuppressive pathways, thereby presenting a more comprehensive attack on the tumor.
"This approach holds immense promise for delivering safer and more potent treatments for glioblastoma, and potentially for other cancers that exhibit resistance to conventional immunotherapies," Dr. Stegh stated. "It represents a critical milestone on the path toward clinical translation and offers tangible hope to patients facing this devastating diagnosis."
Funding and Disclosure: Transparency in Research
The development of this innovative nanotherapy was made possible through substantial financial support from various national and institutional grants. Key funding sources included grants from the National Cancer Institute of the National Institutes of Health (NIH) under award numbers P50CA221747 and R01CA275430, as well as additional NIH grants R01CA120813, R01NS120547, and R01CA272639. Further support was provided by the Melanoma Research Foundation, the Chicago Cancer Baseball Charities at the Lurie Cancer Center of Northwestern University, and grants from industry partners 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, and the National Cancer Institute Cancer Center grant P30CA091842. PET and MRI imaging capabilities were funded by the Robert H. Lurie Comprehensive Cancer Center Grant P30CA060553.
It is important to note that the content presented in this article is solely the responsibility of the authors and does not necessarily reflect the official policies or viewpoints of the NIH.
In terms of potential conflicts of interest, Alexander Stegh, PhD, holds a shareholder position in Exicure Inc., a company actively engaged in the development of SNA therapeutic platforms. Chad A. Mirkin, PhD, is a shareholder in Flashpoint, a company focused on developing therapeutics based on SNA technology. Both Dr. Stegh and Dr. Mirkin are co-inventors on patent US20150031745A1, which outlines the design and application of SNA nanoconjugates for crossing the blood-brain barrier. These disclosures ensure transparency regarding any financial interests that might be perceived to influence the research findings.
