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

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 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 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.