Onion-derived exosome-like nanoparticles transport novel-miR-75-5p to inhibit N-methyl-N′-nitro-N-nitrosoguallidine-induced gastric carcinogenesis by targeting YPEL2/TEM1

Gastric cancer is a malignant tumor that severely threat to human health worldwide. Onions ( Allium cepa L. ), as a common dietary source, offer a promising candidate for exploring natural approaches to cancer chemoprevention and therapy through their bioactive components. Plant-derived exosome-like nanoparticles are attracting growing interest as a novel strategy in the plant-based chemoprevention and treatment of cancers. This study established a malignant transformation model using N-methyl-N’-nitro-N-nitrosoguallidine (MNNG)-treated human gastric mucosa epithelial cells (GES-1) and investigated the protective effects of onion-derived exosome-like nanoparticles (OELNs) in gastric carcinogenesis. Chronic MNNG exposure induced malignant transformation in GES-1 cells, characterized by EMT and increased proliferation. OELNs effectively suppressed oncogenic phenotypes, including proliferation and EMT. Small RNA sequencing identified novel-miR-75-5p as a key miRNA in OELNs, which directly targeted YPEL2 to inhibit gastric carcinogenesis. Functional studies demonstrated that YPEL2 knockdown mimicked the tumor-suppressive effects of OELNs, while YPEL2 overexpression promoted the progression of gastric cancer. RNA sequencing and co-immunoprecipitation revealed YPEL2’s interaction with TEM1, further elucidating its role in gastric carcinogenesis. Additionally, engineered OELNs loaded with novel-miR-75-5p exhibited enhanced anti-tumor activity in cell models and mouse models. These findings highlight the therapeutic potential of OELNs and the OELNs/novel-miR-75-5p/YPEL2 axis in gastric cancer chemoprevention. Schematic diagram of OELNs transporting novel-miR-75-5p to inhibit MNNG induced gastric cancer by targeting YPEL2/TEM1. This figure was drawn using biorender and obtained publishing permission. • Onion-derived exosome-like nanoparticles (OELNs) inhibit N-methyl-N’-nitro-N-nitrosoguallidine (MNNG)-induced malignant transformation and EMT in GES-1 cells. • novel-miR-75-5p in OELNs suppresses gastric oncogenesis by targeting YPEL2. • Knockdown of YPEL2 mimics the tumor-suppressive effects of OELNs. • YPEL2 interacts with TEM1, revealing a novel mechanistic axis in gastric carcinogenesis. • Engineered OELNs loaded with novel-miR-75-5p show enhanced antitumor efficacy.