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In Situ Deployment of Engineered Extracellular Vesicles into the Tumor Niche via Myeloid-Derived Suppressor Cells
Silvia Duarte-Sanmiguel1, Ana Panic1, Daniel J Dodd1,2
1Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.
Abstract:
Extracellular vesicles (EVs) have emerged as a promising carrier system for the delivery of therapeutic payloads in multiple disease models, including cancer. However, effective targeting of EVs to cancerous tissue remains a challenge. Here, it is shown that nonviral transfection of myeloid-derived suppressor cells (MDSCs) can be leveraged to drive targeted release of engineered EVs that can modulate transfer and overexpression of therapeutic anticancer genes in tumor cells and tissue. MDSCs are immature immune cells that exhibit enhanced tropism toward tumor tissue and play a role in modulating tumor progression. Current MDSC research has been mostly focused on mitigating immunosuppression in the tumor niche; however, the tumor homing abilities of these cells present untapped potential to deliver EV therapeutics directly to cancerous tissue. In vivo and ex vivo studies with murine models of breast cancer show that nonviral transfection of MDSCs does not hinder their ability to home to cancerous tissue. Moreover, transfected MDSCs can release engineered EVs and mediate antitumoral responses via paracrine signaling, including decreased invasion/metastatic activity and increased apoptosis/necrosis. Altogether, these findings indicate that MDSCs can be a powerful tool for the deployment of EV-based therapeutics to tumor tissue.
Insights
Myeloid-derived suppressor cells (MDSCs) can be engineered to deliver therapeutic extracellular vesicles (EVs) directly to tumors. This approach enhances targeted gene delivery and exhibits anti-cancer effects in preclinical models.
Area of Science:
- Biomedical Engineering
- Cancer Therapeutics
- Immunology
Background:
- Extracellular vesicles (EVs) show promise as therapeutic delivery systems for cancer.
- Targeting EVs to cancerous tissue is a significant challenge in current cancer therapy.
- Myeloid-derived suppressor cells (MDSCs) possess inherent tumor-homing capabilities.
Purpose of the Study:
- To investigate the potential of using nonvirally transfected MDSCs for targeted delivery of engineered EVs to tumor tissues.
- To evaluate the therapeutic efficacy of MDSC-delivered EVs in a murine breast cancer model.
Main Methods:
- Nonviral transfection of MDSCs with genetic material for engineered EV production.
- In vivo and ex vivo studies using murine models of breast cancer.
- Assessment of MDSC tumor homing ability post-transfection.
- Analysis of EV-mediated antitumoral responses, including gene modulation, invasion, apoptosis, and necrosis.
Main Results:
- Nonviral transfection of MDSCs did not impair their ability to home to cancerous tissue.
- Transfected MDSCs successfully released engineered EVs.
- MDSC-delivered EVs mediated antitumoral responses, reducing invasion and metastasis while increasing apoptosis and necrosis.
Conclusions:
- MDSCs can serve as effective carriers for targeted delivery of EV-based therapeutics to tumor sites.
- This strategy leverages MDSC tropism for enhanced cancer gene therapy.
- MDSC-mediated EV delivery offers a novel approach for developing targeted cancer treatments.
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