Highly Efficient Delivery of Novel MiR-13896 by Human Umbilical Cord Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Inhibits Gastric Cancer Progression by Targeting ATG2A-Mediated Autophagy

Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite recent advancements, clinical outcomes for GC remain unsatisfactory. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have shown promise in inhibiting tumor progression, but their role in GC, specifically human umbilical cord MSC-derived small EVs (hucMSC-sEVs), is not well understood. This study investigates the therapeutic potential of hucMSC-sEVs in GC treatment. We found that hucMSC-sEVs are captured by GC cells, substantially inhibiting their proliferation and inducing apoptosis. MiRNA sequencing revealed that hucMSC-sEVs were enriched with miRNAs having anticancer properties. Among these, miR-13896, a new miRNA, was identified as a potent inhibitor of GC cell proliferation and a promoter of apoptosis. Mechanistic studies revealed that miR-13896 targets and down-regulates the ATG2A-mediated autophagy pathway, suppressing GC cell growth and metastasis. Furthermore, we enriched hucMSC-sEVs with miR-13896 through electroporation. These engineered EVs specifically targeted tumor sites and significantly reduced GC cell growth and migration in vitro and in vivo. MiR-13896 emerged as a promising therapeutic target for GC. The delivery of miR-13896 via hucMSC-sEVs represents a novel and effective strategy for GC treatment, highlighting the potential of EV-based therapies to combat this malignancy.