Multifunctional exosomes inhibiting autophagy ameliorate immune tolerance in non-small cell lung cancer II
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: RNA sequencing of paraffin-embedded tumor biopsy specimens from six NSCLC patients who subsequently underwent anti-PD-L1 neoadjuvant immunotherapy