Nanomedicine-enabled epigenetic therapy for glioblastoma: Overcome the blood-brain barrier and therapeutic resistance

Glioblastoma (GBM), the most aggressive form of primary brain cancer,continues to pose a formidable clinical challenge due to its dismal prognosis and resistance to standard therapy. A recent comprehensive review published in Nano Research underscores the transformative potential of combining nanomedicine with epigenetic therapy to address the core obstacles in GBM treatment, opening new avenues for patient care.

Current standard interventions—surgery, radiation, and chemotherapy—are significantly limited by the diffuse infiltrative growth of GBM, intrinsic radioresistance, and the impermeable blood-brain barrier (BBB) that restricts drug delivery. "The complexity of GBM, from its heterogeneous nature to the presence of therapy-resistant stem cells, has left survival rates largely unchanged despite extensive research efforts" explains Jianshu Li, one of the corresponding authors. Epigenetic alterations, particularly aberrant methylation, are recognized as key drivers of GBM progression and treatment resistance. However, existing epigenetic modulators are hampered by poor solubility, low bioavailability, and off-target effects.

The central proposal of the review is to integrate epigenetic modulators with advanced nanotechnology. "Nanocarriers address the major pharmacokinetic and targeting limitations of epigenetic agents," notes co-corresponding author Wei Wu. Precisely engineered nanoparticles (NPs) can improve drug stability, prolong systemic circulation, and exploit passive or active targeting mechanisms to achieve tumor-selective accumulation. Crucially, specialized nanosystems can traverse the BBB—either through receptor-mediated transcytosis or biomimetic camouflage—and release their payload in response to tumor microenvironment cues like acidic pH.

Examples include folate acid-modified NPs for targeting GBM cells, cell membrane-coated biomimetic nanocarriers with low immunogenicity, and theranostic platforms that combine imaging and therapeutic functions. When loaded with epigenetic drugs such as DNA methyltransferase inhibitors (DNMTis) or histone deacetylase inhibitors (HDACis), these nanosystems can reactivate silenced tumor suppressor genes, sensitize tumors to chemo- and radiotherapy, and reprogram the immunosuppressive tumor microenvironment.

"Our review presents a synergistic treatment paradigm: nanodelivered epigenetic therapy in combined with chemotherapy, radiotherapy, or immunotherapy," says  co-corresponding author Maolan Zhang. This multimodal strategy aims to tackle GBM heterogeneity and overcome drug resistance by concurrently targeting multiple pathological pathways.

Despite the promising outlook, several challenges remain, including immune clearance of NPs, heterogeneous intratumoral distribution, and long-term safety. The authors emphasize the importance of personalizing treatment strategies based on methylation profiling and multi-omics data. "The ultimate goal is to translate these nanoplatforms into clinical practice, moving away from a one-size-fits-all approach," Li adds.

Future efforts will focus on refining nanocarrier design for enhanced BBB penetration and tumor targeting, alongside clinical validation of combination therapies. With continued innovation, the integration of nanomedicine and epigenetics holds the potential to redefine GBM treatment, hope for improved survival and quality of life for patients facing this devastating disease.

DOI Link:

https://doi.org/10.26599/NR.2026.94908472

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 18 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 8,000 articles. In 2025 InCites Journal Citation Reports, its 2025 IF is 9.4 (8.3, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.