Gene-regulation nanotherapy improves survival in mice with glioblastoma

Researchers at Northwestern University have demonstrated a promising gene-regulation therapy that significantly improves survival in mice with glioblastoma multiforme (GBM), an aggressive and currently incurable brain cancer. Using a nanotechnology-based drug designed to silence a cancer-driving gene, the team was able to reduce tumor size and extend survival in animal models, providing a clear proof-of-concept for a targeted RNA interference (RNAi) approach to treating brain tumors.

Glioblastoma kills thousands of people each year and resists most conventional therapies. The Northwestern group developed a novel therapeutic built from spherical nucleic acids (SNAs)—small, densely packed shells of nucleic acids that surround a nanoscale gold core. Because of their spherical architecture and high nucleic acid density, these SNAs can cross biological barriers and enter tumor cells more effectively than linear nucleic acids.

In this study the SNAs were programmed with small interfering RNA (siRNA) sequences that target Bcl2Like12, a gene previously identified as being overexpressed in glioblastoma and linked to the tumor’s resistance to treatment. The siRNA shell binds and silences Bcl2Like12, reducing the production of proteins that help cancer cells evade death. Delivered intravenously, the SNAs crossed the blood–brain barrier and accumulated in brain tumors, where they exerted their RNAi activity without detectable toxicity in treated animals.

In mouse experiments, animals receiving the SNA-based RNAi therapeutic showed nearly a 20 percent increase in survival compared with controls, and tumor volumes were reduced three- to fourfold. Those results, reported in Science Translational Medicine, establish an important therapeutic principle: rationally designed nanoparticle conjugates can reach brain tumors systemically and deliver an effective gene-silencing payload.

Chad A. Mirkin, a senior co-author and a leader in nanomedicine, noted that SNAs are a broadly adaptable platform. Invented at Northwestern, these globular DNA and RNA constructs are nontoxic and can be tailored to target many disease-related genes. Alexander H. Stegh, a glioblastoma specialist and co-author, emphasized the clinical relevance: silencing a multifunctional gene like Bcl2Like12 should sensitize tumors to existing therapies and address multiple mechanisms of therapy resistance.

The collaboration paired Mirkin’s established nanostructure platform with Stegh’s molecular oncology expertise. Mirkin’s SNA platform, first developed in 1996, already underpins diagnostic tools and is now demonstrated to function in vivo in the brain, delivering a therapeutic RNAi effect after systemic administration. Stegh’s laboratory provided the cancer biology insight, having identified Bcl2Like12 as an important contributor to glioblastoma aggressiveness.

This work highlights two advantages of gene-regulation nanotechnology: specificity and delivery. The RNA sequence within the SNA is designed to match the disease gene, enabling specificity at the molecular level, while the nanoparticle architecture solves the persistent delivery challenge for nucleic-acid therapeutics, including passage across the blood–brain barrier and uptake into tumor cells.

Next steps and research context

Following these encouraging animal results, the researchers plan to advance the therapeutic toward clinical trials. The study combined efforts across Northwestern’s Evanston and Chicago campuses and benefited from institutional resources, including a Cancer Nanotechnology Center of Excellence. Funding support for aspects of the work came from the National Cancer Institute’s CCNE program and the Defense Advanced Research Projects Agency (DARPA).

The published paper, titled “Spherical Nucleic Acid Nanoparticle Conjugates as an RNAi-Based Therapy for Glioblastoma,” lists Samuel A. Jensen, Emily S. Day and Caroline H. Ko as co-first authors, with Chad A. Mirkin and Alexander H. Stegh as senior authors, along with a multidisciplinary team of researchers from Northwestern University.

This study demonstrates how nanomaterials and RNAi can be combined to target specific genes in a lethal brain cancer, providing a foundation for personalized, gene-directed therapies that may one day improve outcomes for people with glioblastoma.

Keywords: glioblastoma, glioblastoma multiforme, RNA interference, RNAi, spherical nucleic acids, SNAs, nanoparticles, Bcl2Like12, nanomedicine, blood–brain barrier, Northwestern University, Chad Mirkin, Alexander Stegh

Written by Megan Fellman