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Engineered IL-21-Expressing Nanovesicles for Co-Delivery of GOX and Ferrocene to Induce Synergistic Anti-Tumor
Chao Li1, Mengyang Zhou1, Yang Li1
1School of Life Sciences, Anhui Medical University, Hefei, Anhui, 230032, China.
Abstract:
Glucose oxidase (GOX)-induced starvation is a safe treatment for tumor. However, the non-specific targeting of GOX and the plasticity of tumor metabolism lead to toxic side effects and low tumor mortality. Thus, it is necessary to develop a synergistic strategy with high tumor targeting specificity to enhance the mortality of GOX. In this study, a genetically engineered CD44 targeting peptide (CP) and IL-21 fusion protein-displaying nanovesicles platform (mCP@IL21-Fc-GOX) are designed to efficiently encapsulate GOX and ferrocene (Fc). After reaching the tumor site, IL-21 can be precisely released and targeted to NK cells through the cleavage of MMP-2, thus achieving precise anti-tumor immunotherapy of IL-21. Second, the exposed CP enable mCP-Fc-GOX to be further targeted to tumor cells, completing the synergistic anti-cancer effects of starvation and chemodynamic therapy (CDT) triggered by GOX and Fc. In situ breast cancer models, the results show that mCP@IL21-Fc-GOX not only enhances NK and T cells aggregation in tumor tissue but also achieves precise nutrition deprivation and abundant reactive oxygen species production, thus significantly inhibits tumor growth based on the synergistic function of the immunotherapy, starvation and CDT. Therefore, this work provides a smart nanovesicle platform for achieving precise and safe synergistic anti-tumor therapy.
Insights
This study introduces a smart nanovesicle platform for enhanced cancer therapy. It combines glucose oxidase (GOX) starvation, immunotherapy, and chemodynamic therapy for precise tumor targeting and increased mortality.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Glucose oxidase (GOX) shows promise for tumor starvation therapy but lacks specificity, leading to side effects.
- Tumor metabolism plasticity and non-specific GOX targeting limit treatment efficacy and increase toxicity.
- A synergistic strategy with high tumor specificity is needed to improve GOX-based cancer treatments.
Purpose of the Study:
- To develop a novel nanovesicle platform for targeted synergistic cancer therapy.
- To enhance tumor cell mortality by combining starvation, immunotherapy, and chemodynamic therapy.
- To improve the safety and efficacy of GOX-induced starvation therapy.
Main Methods:
- Engineered CD44 targeting peptide (CP) and IL-21 fusion protein-displaying nanovesicles (mCP@IL21-Fc-GOX) were designed to encapsulate GOX and ferrocene (Fc).
- IL-21 release was triggered by MMP-2 cleavage for targeted NK cell immunotherapy.
- CP facilitated targeting of nanovesicles to tumor cells for combined starvation and chemodynamic therapy (CDT).
Main Results:
- The mCP@IL21-Fc-GOX platform demonstrated enhanced aggregation of NK and T cells in tumor tissues.
- Precise nutrition deprivation and significant reactive oxygen species (ROS) production were achieved.
- Tumor growth was significantly inhibited due to the synergistic effects of immunotherapy, starvation, and CDT.
Conclusions:
- The developed nanovesicle platform offers a precise and safe approach for synergistic anti-tumor therapy.
- This strategy effectively combines immunotherapy, starvation, and CDT for enhanced cancer treatment.
- The smart nanovesicle platform holds potential for future cancer therapeutic applications.
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