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Exosome-Mediated RUNX3 DNA Delivery for Lung Cancer Therapy
Jieun Jeon1,2, Hayeon Byun1, Myung Chul Lee1,3,4
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, United States.
Abstract:
Gene therapy represents a promising strategy for treating lung cancer, with the potential to inhibit the proliferation of cancerous cells and induce apoptosis. However, current gene therapy for lung cancer encounters challenges with delivery, targeting, and safety, such as off-target effects, immune responses, and the necessity for better delivery methods. Here, we introduce gene therapy using the key regulator in lung adenocarcinoma, runt-related transcription factor 3 (RUNX3), within exosomes (Exos), which are known for their biocompatibility and ability to selectively target cancer cells. We packaged the RUNX3 plasmid DNA into human exosomes (hExo-Rs), designed to target and induce apoptosis in cancer cells, resulting in a viability decrease to 43.3%. Normal fibroblasts remained viable at 96.0%, confirming the safety of hExo-Rs for future therapies. We delivered hExo-Rs to cancer spheroids, examined their effects, and found that cytokines from treated cells promote M1 macrophage polarization, emphasizing their potential for immunotherapy. We developed a hydrogel platform for the targeted 14-day release of RUNX3 pDNA by attaching hExo-Rs to gelatin using microbial transglutaminase, which enables the selective decrease in cancer cell viability and confirms apoptosis. Our demonstration of RUNX3 gene therapy with Exos presents selective anticancer effectiveness and the promise of clinical use through localized, sustained release using the hydrogel.
Insights
This study introduces a novel lung cancer gene therapy using RUNX3 delivered via exosomes, showing significant cancer cell death and minimal impact on normal cells. A hydrogel platform ensures sustained release for potential clinical application.
Area of Science:
- Biomedical Engineering
- Oncology
- Gene Therapy
Background:
- Lung cancer gene therapy faces challenges in delivery, targeting, and safety.
- Exosomes offer biocompatible and cancer-cell-targeting delivery potential.
Purpose of the Study:
- To develop and evaluate exosome-mediated RUNX3 gene therapy for lung adenocarcinoma.
- To assess the safety and efficacy of RUNX3-loaded exosomes (hExo-Rs) in vitro and in cancer spheroids.
- To create a hydrogel platform for sustained release of hExo-Rs.
Main Methods:
- Packaging RUNX3 plasmid DNA into human exosomes (hExo-Rs).
- Evaluating hExo-Rs' effect on lung cancer cell viability and apoptosis.
- Assessing hExo-Rs' impact on normal fibroblast viability.
- Analyzing cytokine-induced M1 macrophage polarization post-treatment.
- Developing a gelatin hydrogel for 14-day sustained release of hExo-Rs.
Main Results:
- hExo-Rs decreased cancer cell viability to 43.3% while normal fibroblasts remained at 96.0% viability.
- Treated cancer cells released cytokines that promoted M1 macrophage polarization.
- The hydrogel platform enabled targeted, 14-day sustained release of RUNX3 pDNA.
- Selective decrease in cancer cell viability and confirmed apoptosis were observed with the hydrogel system.
Conclusions:
- Exosome-mediated RUNX3 gene therapy demonstrates selective anticancer effectiveness.
- The developed hydrogel platform facilitates localized, sustained release for potential clinical translation.
- This approach shows promise for safe and effective lung cancer treatment and immunotherapy.
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