By Nana O 
Researchers at Washington University School of Medicine in St. Louis, in collaboration with scientists at Northwestern University, have unveiled a revolutionary noninvasive treatment strategy targeting glioblastoma, one of the most aggressive and deadly forms of brain cancer. This innovative approach leverages precisely engineered nanostructures, composed of minuscule materials, capable of delivering potent cancer-fighting compounds directly into the brain via simple nasal drops. Pre-clinical studies conducted on mice have demonstrated significant success in treating glioblastoma by effectively stimulating the brain’s own immune system, a critical advancement that circumvents the highly invasive procedures often associated with current experimental treatments.
A Paradigm Shift in Glioblastoma Treatment
The findings, published this month in the prestigious journal PNAS (Proceedings of the National Academy of Sciences), represent a significant leap forward in the fight against a disease that has long eluded effective therapeutic interventions. Glioblastoma, originating from astrocytes—a crucial type of brain cell—is the most prevalent and virulent malignant brain tumor in adults, affecting approximately three in every 100,000 individuals in the United States. Its rapid progression and consistently grim prognosis underscore the urgent need for novel treatment modalities. A primary impediment to successful treatment has been the formidable challenge of delivering therapeutic agents across the blood-brain barrier, a highly selective physiological barrier that protects the brain from circulating toxins but also restricts the passage of beneficial drugs.
Dr. Alexander H. Stegh, a professor and vice chair of research in the WashU Medicine Taylor Family Department of Neurosurgery and a co-corresponding author of the study, articulated the driving force behind this research: "We wanted to change this reality and develop a noninvasive treatment that activates the immune response to attack glioblastoma. With this research, we’ve shown that precisely engineered nanostructures, called spherical nucleic acids, can safely and effectively activate powerful immune pathways within the brain. This redefines how cancer immunotherapy can be achieved in otherwise difficult-to-access tumors." Dr. Stegh also holds a pivotal role as the research director of The Brain Tumor Center at Siteman Cancer Center, a joint initiative of Barnes-Jewish Hospital and WashU Medicine.
The Challenge of Glioblastoma and the Promise of Immunotherapy
Glioblastoma is notoriously characterized as a "cold tumor," meaning it largely evades detection and engagement by the body’s immune system. Unlike "hot tumors," which naturally elicit a robust immune response and are more amenable to existing immunotherapies, glioblastoma employs sophisticated mechanisms to suppress immune activity. This immune evasion poses a significant hurdle for therapeutic strategies that rely on the body’s natural defenses.
Scientists have been intensely exploring ways to overcome this challenge, with a particular focus on stimulating a critical cellular pathway known as STING (stimulator of interferon genes). The STING pathway is a vital component of the innate immune system, designed to detect the presence of foreign DNA within cells. Upon activation, it triggers a cascade of immune responses, including the production of interferons, which are crucial for initiating an anti-viral and anti-cancer defense.
Previous research had established that drugs capable of activating the STING pathway could potentially prime the immune system to recognize and attack glioblastoma cells. However, these drugs typically suffer from rapid degradation in the body and necessitate direct injection into the tumor to achieve therapeutic concentrations. Given that glioblastoma often requires multiple treatment sessions, this approach translates into a series of highly invasive surgical procedures, placing a substantial burden on patients already grappling with a severe illness.
Akanksha Mahajan, PhD, a postdoctoral research associate in Dr. Stegh’s lab and the first author of the study, highlighted the impetus for pursuing a less invasive method: "We really wanted to minimize patients having to go through that when they are already ill, and I thought that we could use the spherical nucleic acid platforms to deliver these drugs in a noninvasive way."
Spherical Nucleic Acids: A Novel Delivery System
To address the limitations of previous STING-activating therapies, the research team at Washington University School of Medicine joined forces with Dr. Chad A. Mirkin, PhD, a renowned leader in nanotechnology at Northwestern University. Dr. Mirkin, director of the International Institute for Nanotechnology and the Rathmann Professor of Chemistry, is a pioneer in the development of spherical nucleic acids (SNAs). SNAs are a class of nanoscale particles characterized by a dense arrangement of DNA or RNA molecules on their surface, which has been demonstrated to confer superior efficacy compared to conventional drug delivery systems.
Together, the collaborative teams engineered a specialized form of SNAs for this specific application. These nanostructures feature a core composed of gold nanoparticles, which serve as a stable scaffold, and are densely functionalized with short DNA fragments designed to specifically activate the STING pathway within targeted immune cells. The critical innovation lies in the chosen route of administration: simple nasal drops. This strategy capitalizes on the direct olfactory pathway that connects the nasal passages to the brain, bypassing the blood-brain barrier entirely.
While intranasal delivery has been explored previously for brain-targeted treatments, this marks the first instance where a nanoscale therapeutic has successfully demonstrated the ability to induce potent immune responses against brain tumors using this noninvasive route. "This is the first time that it has been shown that we can increase immune cell activation in glioblastoma tumors when we deliver nanoscale therapeutics from the nose to the brain," Mahajan stated, underscoring the novelty of their findings.
Visualizing Nanostructure Migration and Immune Activation
A key aspect of the research involved meticulously tracking the nanostructures to confirm their precise destination and verify the intended therapeutic effect. To achieve this, the researchers incorporated a molecular tag into the spherical nucleic acids that emits a detectable glow under near-infrared light. Following the administration of these "nanodrops" to mice bearing glioblastoma tumors, the scientists observed the particles migrating along the established olfactory nerve pathway, which directly links the nasal cavity to the brain.
Upon reaching the brain, the immune response triggered by the nanomedicine was observed to concentrate within specific immune cells located in and around the tumor microenvironment. Furthermore, some immune activity was detected in nearby lymph nodes, suggesting a systemic priming of the immune system. Crucially, the therapy did not exhibit widespread distribution throughout the body, thereby minimizing the potential for off-target effects and adverse reactions, a significant concern with many cancer therapies.
Subsequent detailed examination confirmed that immune cells within and adjacent to the glioblastoma tumor had successfully activated the STING pathway. This activation endowed these immune cells with enhanced capabilities, enabling them to mount a more vigorous and effective attack against the cancerous cells.
Synergistic Therapies for Tumor Eradication and Long-Term Protection
The research further explored the potential of combining this novel nanotherapy with other immune-boosting agents. When the STING-activating nanodrops were administered in conjunction with medications designed to activate T lymphocytes—another critical component of the adaptive immune system—the two-dose treatment regimen proved highly effective in eliminating established tumors in the mouse models. Remarkably, this synergistic approach also generated long-lasting immunity, preventing the cancer from recurring in the treated animals. These outcomes significantly surpassed the efficacy observed with current STING-targeting therapies.
Dr. Stegh cautioned that stimulating the STING pathway alone may not be sufficient to achieve a complete cure for glioblastoma, acknowledging that the tumor employs multiple strategies to suppress immune responses. His team is actively investigating methods to incorporate additional immune-activating functionalities directly into their nanostructure designs. This approach could enable the simultaneous targeting of multiple therapeutic pathways within a single treatment, offering a more comprehensive and potent anti-cancer strategy.
"This is an approach that offers hope for safer, more effective treatments for glioblastoma and potentially other immune treatment-resistant cancers, and it marks a critical step toward clinical application," Dr. Stegh affirmed, expressing optimism about the future clinical translation of this technology.
Broader Implications and Future Directions
The implications of this research extend beyond glioblastoma. The development of a noninvasive, brain-penetrating nanodelivery system that can activate the immune system holds immense promise for treating a range of neurological disorders and other cancers that are difficult to access with conventional therapeutics. The ability to precisely target immune pathways within the brain, while minimizing systemic exposure, represents a significant advancement in drug delivery and cancer immunotherapy.
The success of this study in mice provides a strong foundation for future clinical trials in humans. The research team is expected to pursue further investigations to optimize dosage, assess long-term safety, and evaluate efficacy in human patients. The potential to transform the treatment landscape for glioblastoma patients, offering a less burdensome and more effective therapeutic option, is substantial. This pioneering work underscores the power of interdisciplinary collaboration and the transformative potential of nanotechnology in addressing some of medicine’s most formidable challenges.
Study Funding and Acknowledgements
This groundbreaking research was made possible through substantial support from various national and institutional funding bodies. Key contributions came from the National Cancer Institute (NCI) of the National Institutes of Health (NIH) through grant 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. Specialized 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. Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) were supported by the Robert H. Lurie Comprehensive Cancer Center Grant P30CA060553. The content of this publication is solely the responsibility of the authors and does not necessarily reflect the official views of the NIH.
Disclosure of Competing Interests
The researchers involved have disclosed potential conflicts of interest that are managed to ensure scientific integrity. Dr. Alexander Stegh is a shareholder of Exicure Inc., a company engaged in the development of 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 describes the use of SNA nanoconjugates for crossing the blood-brain barrier. These disclosures are made in accordance with scientific and ethical guidelines to ensure transparency in research reporting.
