By Nana O 
Researchers at Washington University School of Medicine in St. Louis, in collaboration with scientists from Northwestern University, have unveiled a groundbreaking noninvasive strategy poised to transform the treatment landscape for glioblastoma, one of the most aggressive and lethal forms of brain cancer. This innovative approach leverages precisely engineered nanostructures, delivered via simple nasal drops, to ferry potent cancer-fighting compounds directly into the brain. In preclinical studies conducted on mice, this novel method has demonstrated remarkable success in combating glioblastoma by effectively stimulating the brain’s own immune system, offering a less invasive alternative to current experimental treatments. The findings, published this month in the prestigious journal Proceedings of the National Academy of Sciences (PNAS), mark a significant leap forward in the quest for effective glioblastoma therapies.
The Elusive Nature of Glioblastoma: A Persistent Challenge in Oncology
Glioblastoma, a devastating malignancy originating from astrocytes—a crucial type of brain cell—stands as the most prevalent and aggressive primary malignant brain tumor. Affecting approximately three out of every 100,000 individuals in the United States annually, its rapid progression and grim prognosis make it a formidable adversary. A primary impediment to developing successful treatments has long been the inherent difficulty in delivering therapeutic agents across the formidable blood-brain barrier, a highly selective physiological barrier that protects the central nervous system from circulating toxins and pathogens, but also severely restricts the passage of most medications.
"Our core objective was to fundamentally alter this challenging reality by devising a noninvasive treatment modality capable of harnessing and activating the immune response to specifically target and eradicate glioblastoma," 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 holds the esteemed position of research director for The Brain Tumor Center at Siteman Cancer Center, a joint initiative of Barnes-Jewish Hospital and WashU Medicine, elaborated, "Through this comprehensive research, we have conclusively demonstrated that exquisitely engineered nanostructures, specifically spherical nucleic acids (SNAs), possess the remarkable ability to safely and efficiently stimulate potent immune pathways within the brain. This breakthrough fundamentally redefines the paradigm for achieving cancer immunotherapy in tumors that have historically proven exceptionally difficult to access."
Reactivating the Immune System: The Power of STING Pathway Nanomedicine
Glioblastoma tumors are notoriously characterized as "cold tumors," a designation stemming from their inherent ability to evade detection and provoke a robust immune response. Unlike "hot tumors," which are more susceptible to immunotherapies due to their inflammatory microenvironment and presence of immune cells, glioblastoma actively suppresses antitumor immunity. Scientists have been actively investigating strategies to overcome this immune evasion, with a particular focus on stimulating a critical cellular signaling pathway known as STING (stimulator of interferon genes). The STING pathway is a key component of the innate immune system, designed to detect the presence of foreign DNA—such as that from viruses or bacteria—and initiate a cascade of immune defenses, including the production of interferons, which are vital for antiviral and antitumor responses.
Prior investigations had indicated that drugs designed to activate the STING pathway could effectively prime the immune system to recognize and attack glioblastoma. However, these drugs faced significant limitations: they exhibited rapid degradation in the body, necessitating direct injection into the tumor for optimal efficacy. Given that multiple doses are typically required for a meaningful therapeutic effect, this approach inherently involves highly invasive surgical procedures, posing considerable risks and discomfort to already vulnerable patients.
"Our paramount concern was to mitigate the need for patients to undergo such invasive procedures, especially when they are already grappling with a severe illness," explained Dr. Akanksha Mahajan, a postdoctoral research associate in Dr. Stegh’s laboratory and the first author of the study. "This led us to explore the potential of spherical nucleic acid platforms as a means to deliver these potent STING-activating drugs in a completely noninvasive manner."
Engineering Nanostructures for Nose-to-Brain Delivery: A Fusion of Gold and DNA
To surmount the delivery challenges, Dr. Stegh’s team forged a crucial partnership with Dr. Chad A. Mirkin, PhD, a leading figure in nanotechnology and the director of the International Institute for Nanotechnology and the Rathmann Professor of Chemistry at Northwestern University. Dr. Mirkin is renowned for his pioneering work in the development of spherical nucleic acids (SNAs), a class of nanoscale particles characterized by a dense arrangement of DNA or RNA molecules encircling a core. These unique structures have demonstrated superior efficacy in drug delivery compared to conventional delivery systems.
The collaborative effort resulted in the design of a specialized iteration of SNAs. These nanostructures feature a core composed of gold nanoparticles, renowned for their biocompatibility and ease of functionalization, densely coated with short DNA fragments engineered to specifically activate the STING pathway within targeted immune cells. The critical innovation lay in their method of delivery: the nasal passages were ingeniously utilized as a direct conduit for transporting these therapeutic nanostructures into the brain.
While intranasal delivery has been explored previously for brain-targeted treatments, this research marks a significant milestone as it is the first to demonstrate the ability of a nanoscale therapeutic, delivered via this route, to effectively activate immune responses specifically against brain tumors.
"This represents a groundbreaking achievement; it is the first time we have successfully shown that we can enhance immune cell activation within glioblastoma tumors by delivering nanoscale therapeutics from the nose directly to the brain," Dr. Mahajan emphasized, highlighting the novelty and potential of their work.
Tracing the Journey: Nanodrops Navigate to the Brain
A key objective for the researchers was to rigorously confirm both the selective targeting of the brain and the precise activation of the intended immune cells. To achieve this, they incorporated a molecular tag into the spherical nucleic acids that emits a fluorescent signal detectable under near-infrared light. Following the administration of these nanodrops to mice experimentally induced with glioblastoma, the research team meticulously tracked the particles’ movement. Their observations revealed that the nanostructures traveled efficiently along the olfactory nerve pathway, the primary neural tract connecting the nasal cavity to the brain.
Upon reaching their destination within the brain, the nanomedicine-induced immune response was observed to concentrate with remarkable specificity in particular immune cells residing within the tumor microenvironment. A degree of immune activity was also detected in adjacent lymph nodes, suggesting a systemic priming effect. Crucially, the therapy did not exhibit widespread dissemination throughout the body, a factor that significantly mitigates concerns about potential off-target effects and adverse reactions.
Further in-depth analysis confirmed that immune cells located within and surrounding the glioblastoma tumor had successfully activated the STING pathway. This activation empowered these immune cells to mount a more formidable and coordinated attack against the cancerous cells, leading to a reduction in tumor burden.
A Synergistic Approach: Eradicating Tumors and Preventing Recurrence
The true potential of this nanotherapy was illuminated when it was combined with therapeutic agents designed to activate T lymphocytes, another critical class of immune cells crucial for adaptive immunity. This dual-treatment regimen, administered in two doses, resulted in the complete eradication of tumors in the mouse models. More remarkably, it induced a long-lasting immunological memory, effectively preventing the cancer from recurring. These outcomes surpassed those achieved with existing STING-targeting therapies by a significant margin, underscoring the enhanced efficacy of the nanostructure-based approach.
Dr. Stegh cautioned, however, that stimulating the STING pathway alone may not be sufficient to achieve a complete cure for glioblastoma. He explained that the tumor employs a multifaceted array of defense mechanisms to suppress or shut down immune surveillance. To address this, his research group is actively exploring strategies to incorporate additional immune-activating functionalities directly into their nanostructures. Such an integrated approach could enable the simultaneous targeting of multiple therapeutic pathways within a single, comprehensive treatment.
"This represents a promising avenue that offers substantial hope for the development of safer and more efficacious treatments for glioblastoma," Dr. Stegh affirmed. "Furthermore, it holds the potential to benefit patients suffering from other types of cancer that exhibit resistance to conventional immune therapies. This work represents a pivotal stride towards the eventual clinical application of this innovative treatment strategy."
Broader Implications and Future Directions
The implications of this research extend far beyond glioblastoma. The ability to noninvasively deliver therapeutics directly to the brain via nasal drops opens up new possibilities for treating a range of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative conditions. The targeted activation of the immune system also holds promise for other hard-to-treat cancers that currently lack effective therapeutic options.
The successful preclinical demonstration of this nanotherapy provides a strong foundation for future clinical trials. Researchers anticipate that the transition to human studies will be expedited due to the noninvasive nature of the delivery method and the established safety profile of the components used. The next steps will involve refining the nanostructure design, optimizing dosage regimens, and conducting rigorous safety and efficacy evaluations in human patients.
The collaborative spirit between Washington University and Northwestern University, bringing together expertise in neurosurgery, immunology, and nanotechnology, has been instrumental in this breakthrough. This interdisciplinary approach underscores the critical role of cross-institutional collaboration in tackling complex scientific challenges.
Funding and Acknowledgements
This pioneering research was made possible through substantial support from various esteemed organizations. Key funding was provided by the National Cancer Institute of the National Institutes of Health (NIH) under grant numbers P50CA221747 and R01CA275430. Additional support came from the NIH through grants R01CA120813, R01NS120547, and R01CA272639. Further contributions were received 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 infrastructure was supported by the Robert H. Lurie Comprehensive Cancer Center Grant P30CA060553.
It is important to note that the content presented in this publication is solely the responsibility of the study’s authors and does not necessarily reflect the official views or policies of the NIH.
Competing Interests Disclosure
The authors wish to disclose any potential conflicts of interest. Dr. Alexander Stegh holds shares in Exicure Inc., a company actively involved in the development of SNA therapeutic platforms. Dr. Chad Mirkin is a shareholder in Flashpoint, a company that develops SNA-based therapeutics. Both Dr. Stegh and Dr. Mirkin are listed as co-inventors on U.S. Patent Application US20150031745A1, which details the use of SNA nanoconjugates for crossing the blood-brain barrier. These disclosures are made to ensure transparency and uphold the integrity of the research findings.
