Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy

Author:

Kudruk Sergej12ORCID,Forsyth Connor M.12ORCID,Dion Michelle Z.34ORCID,Hedlund Orbeck Jenny K.12ORCID,Luo Jingqin56,Klein Robyn S.78910ORCID,Kim Albert H.511ORCID,Heimberger Amy B.12,Mirkin Chad A.12ORCID,Stegh Alexander H.511,Artzi Natalie413

Affiliation:

1. Department of Chemistry, Northwestern University, Evanston, IL 60208

2. International Institute for Nanotechnology, Northwestern University, Evanston, IL 60208

3. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115

4. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139

5. The Brain Tumor Center, Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110

6. Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110

7. Department of Medicine, Washington University School of Medicine, St. Louis, MO

8. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

9. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110

10. Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO 63110

11. Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110

12. Department of Neurological Surgery, Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

13. Department of Medicine, Engineering in Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02115

Abstract

Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic.

Funder

HHS | NIH | National Cancer Institute

HHS | National Institutes of Health

MIT | Deshpande Center for Technological Innovation, Massachusetts Institute of Technology

BWH | Brigham Research Institute

National Science Foundation

Publisher

Proceedings of the National Academy of Sciences

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