Developing extracellular vesicle-mediated targeted microRNA delivery system for EGFR cancers

Title Developing extracellular vesicle-mediated targeted microRNA delivery system for EGFR cancers Project Summary Targeted therapy acts on a well-defined molecular mechanism of disease pathologies within a tissue or cells. However, many clinical trials encountered insufficient efficacy or safety issues due to accumulating in unwanted

organs or off-target effects. One such molecule, microRNA(miRNA), is a small non-coding RNA that plays a critical role in tumor biology, including tumor progression, drug resistance, and metastasis, through sequence- specific translational regulation. While miRNAs hold a promising therapeutic potential, the adverse events

resulting from severe immunogenic responses terminated the clinical trials. Thus, an efficient delivery system is essential to establishing miRNA therapy. This project aims to establish a targeted therapeutic miRNA delivery system using engineered cell-derived extracellular vesicles (EVs). EVs are the body's natural biomolecular

transporters that could overcome various issues associated with existing delivery systems. Specifically, we will engineer EV surface with antibody mimetics (monobody) to target Epidermal Growth Factor Receptor (EGFR) cancer to deliver tumor suppressor miRNAs. We hypothesize that EVs can efficiently deliver miRNAs into EGFR+

cells, where the miRNAs will exert powerful anti-tumor effects. Following the EV generation, we will demonstrate that these miRNA packaging EVs will have EGFR tumor specificity and anti-tumor effects. This will build a foundation for EV-based targeted delivery of miRNA-based therapies. We expect our approach to offer new

possibilities for cancer treatment by utilizing EVs with low immunogenicity, cytotoxicity, and efficient miRNA release. These validations will empower and accelerate the development of EV-based targeted therapeutic delivery.