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Multifunctional extracellular vesicles inhibiting autophagy ameliorate immunotherapy in non-small cell lung cancer
Simiao Wang1, Jiayi Chen1, Yaxin Cui1
1School of Life Sciences, Jilin University, Changchun 130012, China.
Abstract:
The modulation of tumor autophagy to enhance antitumor immunity has garnered significant attention, underscoring its critical role in cancer immunotherapy. However, advanced strategies for precise autophagy-regulating drug delivery remain a pressing need. Here, we introduce a targeted small extracellular vesicles (sEVs)-based drug delivery system capable of simultaneously loading antibodies and nucleic acid drugs while ensuring their accurate release in the tumor microenvironment (TME). We developed a dual-stimulation electroporation system that integrates nanosecond electric pulses and ultrasound to enhance sEV production, yielding IL-7 mRNA-enriched sEVs that overexpress CD64 receptors for efficient capture of anti-PD-L1 antibodies. These multifunctional autophagy-inhibiting and immunomodulatory sEVs (AI-sEVs) are designed to inhibit autophagy and modulate immune responses in non-small cell lung cancer. Upon delivery to the TME, AI-sEVs mediate the enzymatic cleavage of peptide bonds, releasing IL-7 mRNA. This process induces autophagy suppression and restores MHC-I expression, which synergizes with anti-PD-L1 immune checkpoint inhibition to enhance antitumor efficacy. In conclusion, this study proposes an innovative methodology that utilizes engineered sEVs for the co-delivery of protein antibodies and genetic materials. This approach establishes a promising strategy for advancing cancer immunotherapy by targeting the modulation of autophagy.
Insights
This study developed engineered extracellular vesicles (EVs) to deliver drugs that inhibit tumor autophagy and boost immune responses. This novel approach enhances cancer immunotherapy by combining autophagy suppression with immune checkpoint blockade.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Tumor autophagy modulation is crucial for enhancing antitumor immunity in cancer immunotherapy.
- Advanced drug delivery systems for precise autophagy regulation are needed.
Purpose of the Study:
- To develop a targeted small extracellular vesicles (sEVs)-based drug delivery system for co-delivering antibodies and nucleic acid drugs.
- To engineer sEVs for precise drug release in the tumor microenvironment (TME) to inhibit autophagy and modulate immune responses in non-small cell lung cancer.
Main Methods:
- Developed a dual-stimulation electroporation system (nanosecond electric pulses and ultrasound) to enhance sEV production.
- Engineered sEVs (AI-sEVs) to co-load IL-7 mRNA and anti-PD-L1 antibodies, overexpressing CD64 receptors for antibody capture.
- AI-sEVs were designed to release IL-7 mRNA in the TME via enzymatic cleavage.
Main Results:
- IL-7 mRNA release from AI-sEVs suppressed tumor autophagy and restored MHC-I expression.
- The combined autophagy inhibition and anti-PD-L1 immune checkpoint blockade demonstrated synergistic antitumor efficacy.
- Engineered sEVs successfully co-delivered protein antibodies and genetic materials for targeted cancer therapy.
Conclusions:
- This study presents an innovative methodology using engineered sEVs for co-delivery of therapeutic agents.
- This approach offers a promising strategy for advancing cancer immunotherapy through targeted autophagy modulation.
- The developed AI-sEVs system holds potential for treating non-small cell lung cancer.
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