Scientists from Washington University School of Medicine in St. Louis, in collaboration with experts from Northwestern University, have pioneered a non-invasive technique to combat one of the deadliest and most aggressive types of brain cancer. This innovative approach utilizes meticulously engineered nanostructures composed of ultra-tiny materials that transport powerful anti-cancer agents directly into the brain via straightforward nasal drops. In experiments conducted with mice, the method proved highly effective against glioblastoma by invigorating the brain’s own immune defenses. Notably, this strategy circumvents the invasive procedures associated with other emerging therapies.
The results of this groundbreaking research appeared in the prestigious journal PNAS earlier this month.
Challenges in Treating Glioblastoma Effectively
Glioblastoma arises from astrocytes, which are supportive cells in the brain, and represents the most prevalent form of malignant brain tumor. It impacts approximately three individuals per 100,000 in the United States. This condition progresses swiftly and is nearly invariably lethal. A primary hurdle in its management lies in the difficulty of delivering therapeutic drugs across the blood-brain barrier into the affected brain tissue.
Our goal was to transform this challenging landscape by devising a non-surgical treatment that harnesses the body’s immune system to target glioblastoma, explained Alexander H. Stegh, PhD, who holds positions as a professor and vice chair of research in the Taylor Family Department of Neurosurgery at WashU Medicine, and serves as a co-corresponding author on the paper. Stegh also directs research at The Brain Tumor Center at Siteman Cancer Center, affiliated with Barnes-Jewish Hospital and WashU Medicine. Through this investigation, we have demonstrated that precisely crafted nanostructures, known as spherical nucleic acids, can reliably and potently engage critical immune mechanisms deep within the brain. This advancement reshapes the possibilities for immunotherapy in tumors that are notoriously hard to reach.
Revitalizing Immune Defenses Through STING Pathway Nanomedicine
Glioblastoma is frequently classified as a cold tumor due to its limited capacity to elicit a robust immune reaction. In contrast to hot tumors, which respond well to immunotherapy interventions, glioblastoma skillfully avoids immune surveillance. Researchers have been investigating the STING pathway—standing for stimulator of interferon genes—as a promising target. This cellular pathway springs into action upon detection of foreign DNA, thereby mobilizing comprehensive immune countermeasures.
Prior studies indicated that STING-activating compounds could prepare the immune system to assault glioblastoma cells. However, these agents break down rapidly and necessitate direct injection into the tumor mass for any meaningful impact. Given the requirement for repeated administrations, such methods demand repeated invasive interventions, which pose significant burdens on patients.
We were determined to spare patients these ordeals, particularly when they are already battling serious illness, and believed that spherical nucleic acid platforms offered a viable path for non-invasive drug delivery, stated Akanksha Mahajan, PhD, a postdoctoral research associate in Stegh’s laboratory and the study’s lead author.
Developing Gold-Core Nanostructures for Direct Nose-to-Brain Transport
To overcome these limitations, Stegh’s team joined forces with co-corresponding author Chad A. Mirkin, PhD, who leads the International Institute for Nanotechnology and holds the Rathmann Professorship in Chemistry at Northwestern University. Mirkin is the originator of spherical nucleic acids, which consist of nanoscale particles densely functionalized with DNA or RNA strands. These constructs have consistently outperformed conventional delivery vehicles in efficacy.
The collaborative effort yielded an advanced iteration of spherical nucleic acids, incorporating gold nanoparticle cores paired with concise DNA sequences designed to trigger the STING pathway specifically in immune cells. For brain entry, the nasal route was selected as the optimal portal.
While intranasal administration has been explored previously for brain-directed therapies, no prior nanoscale intervention had successfully provoked anti-tumor immune activation via this pathway.
This marks the inaugural demonstration that nasal delivery of nanoscale therapeutics can heighten immune cell engagement within glioblastoma tumors, as highlighted by Mahajan.
Monitoring the Journey of Nanodrops from Nose to Brain Tissue
The research team sought to validate not only the precise targeting of the brain but also the accurate stimulation of intended immune cells. To this end, they incorporated a fluorescent molecular label into the spherical nucleic acids, visible under near-infrared illumination. Following intranasal application in mice bearing glioblastoma, the nanostructures were tracked progressing along the primary olfactory nerve that links the nasal cavity to the brain.
Upon arrival, the immune activation induced by the nanomedicine localized predominantly to key immune cells embedded within the tumor microenvironment. Traces of activity extended to adjacent lymph nodes. Crucially, systemic dissemination was minimal, thereby mitigating risks of off-target effects and adverse reactions.
Detailed analysis confirmed that immune cells both inside the tumor and in its vicinity had robustly engaged the STING pathway, empowering them to launch a more vigorous offensive against the malignancy.
Integrating Therapies to Eliminate Tumors and Block Recurrence
When the nanotherapy was combined with agents that enhance T lymphocyte activation—essential immune effectors—a mere two-dose regimen completely eradicated tumors in the mouse models. Moreover, it engendered durable immunological memory that thwarted tumor regrowth. These results far surpassed outcomes from existing STING-focused treatments.
Stegh emphasized that STING stimulation in isolation is insufficient to overcome glioblastoma entirely, as the tumor employs multifaceted strategies to suppress immunity. His laboratory is now engineering nanostructures with multifaceted immune-boosting capabilities, enabling simultaneous targeting of diverse therapeutic vulnerabilities via a unified administration.
This methodology holds substantial promise for delivering safer, superior treatments against glioblastoma and other immunotherapy-resistant cancers, representing a pivotal milestone en route to human clinical trials, Stegh affirmed.
