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

Area of Science:

• Biotechnology
• Molecular Biology
• Oncology

Background:

• Targeted drug delivery and oncogene inhibition are critical challenges in cancer treatment.
• Small interfering RNAs (siRNAs) offer therapeutic potential but face delivery limitations, especially in extrahepatic tissues.
• Epidermal Growth Factor Receptor (EGFR) is a key oncogene in various cancers, including Non-Small Cell Lung Cancer (NSCLC).

Purpose of the Study:

• To develop a targeted therapeutic strategy for EGFR-positive tumours using an in vivo self-assembled (IVSA) siRNA delivery system.
• To engineer a genetic circuit for liver-based production and self-assembly of EGFR siRNAs into targeted extracellular vesicles.
• To evaluate the therapeutic efficacy of this IVSA siRNA system in preclinical models of EGFR-driven cancers.

Main Methods:

• Designed an IVSA genetic circuit to reprogram the liver for siRNA production and self-assembly into small extracellular vesicles (sEVs).
• Engineered sEVs with an EGFR-targeting peptide (GE11) for specific delivery to EGFR-positive tumour cells.
• Assessed the therapeutic efficacy in EGFR-driven NSCLC, orthotopic gastric, and breast cancer models.

Main Results:

• The IVSA siRNA system significantly reduced tumour size and suppressed EGFR expression in EGFR-driven NSCLC models.
• This approach demonstrated superior efficacy compared to traditional treatments like gefitinib and osimertinib.
• Significant tumour suppression and enhanced survival outcomes were observed in orthotopic gastric and breast cancer models.

Conclusions:

• The IVSA platform offers a versatile and potent method for targeted siRNA delivery for EGFR-positive cancers.
• This technology provides a promising new therapeutic avenue for treating a range of EGFR-driven malignancies.
• The system overcomes previous delivery barriers, enabling effective extrahepatic siRNA-based cancer therapy.