Multifunctional exosomes inhibiting autophagy ameliorate immune tolerance 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 exosome-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 integrating nanosecond electric pulses and ultrasound to enhance exosome production, yielding IL-7 mRNA-enriched exosomes overexpressing CD64 receptors for efficient anti-PD-L1 antibody capture. These multifunctional autophagy-inhibiting and immunomodulatory exosomes (AI-Exos) are designed to inhibit autophagy and modulate immune responses in lung cancer. Upon delivery to the tumor site, AI-Exos mediate the enzymatic cleavage of peptide bonds to release IL-7 mRNA. This process induces autophagy suppression and restores MHC-I expression, which synergizes with anti-PD-L1 immune checkpoint inhibition to overcome acquired drug resistance and enhance antitumor efficacy. In conclusion, this study proposes an innovative methodology utilizing engineering exosomes for the co-delivery of protein antibodies and genetic materials. This approach establishes a promising strategy to advance cancer immunotherapy through targeted autophagy modulation. Overall design: Single-cell sequencing analysis of immune cells in mouse non-small cell lung cancer after drug treatment.