IVSA-based siRNA targeted delivery system as a universal strategy for the treatment of EGFR-positive cancer.

Achieving precise antitumour drug delivery to tumour sites and selectively inhibiting oncogene function remain core challenges in cancer treatment. While small interfering RNAs (siRNAs) are a powerful means of achieving these goals, their clinical application is limited by delivery barriers, particularly in extrahepatic tissues. Based on the in vivo self-assembled (IVSA) siRNA delivery system, we developed a targeted therapeutic approach for EGFR-positive tumours in this study. We designed an IVSA genetic circuit that can reprogram the liver to produce and self-assemble EGFR siRNAs into small extracellular vesicles (sEVs) tagged with an EGFR-targeting peptide (GE11). The siRNA-encapsulating sEVs can be transported via the blood circulation and guided to EGFR-positive tumour cells by a targeting peptide for tumour therapy. In EGFR-driven NSCLC models, the IVSA siRNA dramatically reduced tumour size and suppressed EGFR expression more effectively than traditional treatments such as gefitinib or osimertinib. We evaluated the efficacy of this system in orthotopic gastric and breast cancer models to further show its therapeutic value for other EGFR-positive tumours. In these models, the IVSA siRNA resulted in significant tumour suppression and enhanced survival outcomes. These findings underscore the versatility and potency of the IVSA platform as a universal therapeutic approach for EGFR-targeted siRNA delivery, providing a promising new avenue for treating a range of EGFR-positive cancers.