Abstract
Glioblastoma (GBM) is among the most aggressive brain tumors, presenting significant therapeutic challenges due to intrinsic and acquired resistance to treatment, alongside a highly immunosuppressive tumor microenvironment (TME). While temozolomide (TMZ) is the standard chemotherapeutic agent with the ability to penetrate the blood-brain barrier (BBB), its clinical efficacy is often limited. Here, we report a strategy employing Apolipoprotein E (ApoE) peptide-functionalized polymersomes loaded with small interfering RNA (siRNA) targeting signal transducer and activator of transcription 3 (Apstat3) to amplify the anti-GBM effects of TMZ and immunotherapy. Apstat3 demonstrated small, uniform particle sizes, stability in siRNA encapsulation, and effective downregulation of STAT3 and O⁶-methylguanine-DNA methyltransferase (MGMT) in GL261 cells, sensitizing these tumor cells to TMZ. The combinatorial approach not only significantly inhibited GBM cell proliferation, migration and invasion but also improved dendritic cells (DCs) maturation under TME-mimicking environment. In orthotopic GL261 mouse models, intravenous injection of Apstat3 co-administered with oral TMZ resulted in a twofold increase in median survival and reshaped the TME. Notably, combined treatment with anti-CTLA4 therapy tripled median survival to 64 days, achieving complete remission observed in 20% of the mice. This siSTAT3 delivery strategy holds promise for enhancing GBM treatment outcomes.
Overview
- The study explores the use of Apolipoprotein E (ApoE) peptide-functionalized polymersomes loaded with small interfering RNA (siRNA) targeting signal transducer and activator of transcription 3 (Apstat3) to amplify the anti-glioblastoma effects of temozolomide (TMZ) and immunotherapy.
- The Apstat3-loaded polymersomes demonstrated small, uniform particle sizes, stability in siRNA encapsulation, and effective downregulation of STAT3 and O⁶-methylguanine-DNA methyltransferase (MGMT) in GL261 cells.
- The study aimed to enhance glioblastoma treatment outcomes by combining siRNA delivery with chemotherapy and immunotherapy to more effectively target the highly immunosuppressive tumor microenvironment (TME) of glioblastoma.
Comparative Analysis & Findings
- The study found that the combinatorial approach significantly inhibited glioblastoma cell proliferation, migration, and invasion compared to TMZ alone.
- In orthotopic GL261 mouse models, the combination of siSTAT3 delivery and TMZ resulted in a twofold increase in median survival compared to TMZ alone.
- The combination of siSTAT3 delivery, TMZ, and anti-CTLA4 therapy tripled median survival to 64 days, achieving complete remission in 20% of the mice.
Implications and Future Directions
- The study's findings suggest that siRNA delivery targeting STAT3 may be a promising strategy for enhancing glioblastoma treatment outcomes, particularly when combined with chemotherapy and immunotherapy.
- Future studies should investigate the optimal dosing and scheduling of siSTAT3 delivery and combination therapies to improve treatment efficacy and minimize side effects.
- The study's results also highlight the importance of understanding the tumor microenvironment and its effects on glioblastoma treatment, and future research may aim to develop strategies to target and modify the TME to improve treatment outcomes.