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RNA Nanoparticle-Based Targeted Therapy for Glioblastoma through Inhibition of Oncogenic miR-21
Tae Jin Lee1, Ji Young Yoo2, Dan Shu3
1Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Abstract:
Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust and efficient delivery platform to successfully inhibit this druggable target. Three-way-junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate (FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.
Insights
Folate-conjugated RNA nanoparticles effectively deliver anti-miR-21 sequences to glioblastoma, inhibiting tumor growth and improving survival. This targeted gene therapy approach shows promise for treating glioblastoma.
Area of Science:
- Biotechnology
- Oncology
- Molecular Biology
Background:
- Oncogenic microRNA-21 (miR-21) drives glioblastoma growth by suppressing tumor suppressors PTEN and PDCD4.
- Effective systemic delivery of anti-miR-21 agents is crucial for glioblastoma treatment.
- Bacteriophage phi29-derived three-way-junction (3WJ) RNA nanoparticles (RNP) show potential for glioblastoma targeting.
Purpose of the Study:
- To develop and evaluate a novel folate-conjugated 3WJ RNP system for targeted delivery of anti-miR-21 locked nucleic acid (LNA) sequences to glioblastoma.
- To assess the efficacy of this system in inhibiting miR-21 expression and promoting glioblastoma cell apoptosis both in vitro and in vivo.
- To determine the therapeutic potential of this gene therapy approach in glioblastoma models.
Main Methods:
- Construction of multi-valent folate (FA)-conjugated 3WJ RNP harboring anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21).
- In vitro and in vivo evaluation of FA-3WJ-LNA-miR21 targeting, delivery, and miR-21 knockdown in glioblastoma cells.
- Assessment of PTEN and PDCD4 rescue, glioblastoma cell apoptosis, tumor growth inhibition, and overall survival in preclinical models.
Main Results:
- FA-3WJ-LNA-miR21 RNP demonstrated specific targeting and efficient delivery of anti-miR-21 LNA to glioblastoma cells.
- Successful knockdown of miR-21 expression was observed in vitro and in vivo.
- Systemic administration of FA-3WJ-LNA-miR21 RNP led to PTEN and PDCD4 rescue, enhanced glioblastoma cell apoptosis, significant tumor growth regression, and improved overall survival.
Conclusions:
- FA-conjugated 3WJ RNP serves as an effective platform for targeted delivery of anti-miR-21 LNA for glioblastoma therapy.
- This approach successfully inhibits oncogenic miR-21, restores tumor suppressors, and exhibits significant anti-tumor activity.
- FA-3WJ RNP-based gene therapy holds clinical promise for treating both developing and recurrent glioblastoma.
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