Engineered lung cell targeting and <scp>SLC7A11 siRNA</scp> expressing bacterial extracellular vesicles impair the progression of none‐small cell lung cancer

Non-small cell lung cancer (NSCLC) presents significant therapeutic challenges, often characterized by aggressive proliferation and metastasis. This study investigates the role of SLC7A11, a ferroptosis-related gene, in NSCLC progression and the potential of engineered bacterial extracellular vesicles (BEVs) expressing SLC7A11-targeting siRNA as a therapeutic strategy. Using TCGA and GEO databases, we identified that SLC7A11 was significantly upregulated in NSCLC tissues. Functional assays demonstrated that SLC7A11 knockdown in NSCLC cell lines (NCI-H2122 and NCI-H647) via qPCR, Western blot, and immunofluorescence resulted in impaired proliferation, migration, and invasion abilities. In vivo xenograft models further revealed that SLC7A11 knockdown inhibited tumor growth and metastasis, corroborated by histological analyses. To enhance targeted delivery of SLC7A11 siRNA, we engineered BEVs with a lung cell targeting peptide, verifying their structure and function through transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). In vivo toxicity assessments indicated safety for these bioengineered vesicles. Importantly, treatment with BEVs-LCTP-siSLC7A11 not only impaired tumorigenesis but also activated ferroptosis pathways, as evidenced by altered expression levels of SLC7A11 and transferrin in tumor and metastatic tissues. Our findings suggest that targeting SLC7A11 through engineered BEVs presents a promising approach to inhibit NSCLC progression while activating ferroptosis, offering insights into novel therapeutic strategies against lung cancer.