Multifunctional extracellular vesicles inhibiting autophagy ameliorate immunotherapy in non-small cell lung cancer

作者：Simiao Wang, Jiayi Chen, Yaxin Cui, Jianming Xing, Jiayi Liu, Hao Jiang, Hongqun Yang, Huan Zhang, Man Sun, Jialin Li, Wei Liu, Zhou Chen, Wei Sun, Xiaobing Wang, Zhaogang Yang · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.12.013 · 被引用次数：7 · 研究领域：Extracellular vesicles in disease、Nanoplatforms for cancer theranostics、Autophagy in Disease and Therapy

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.