Non-small cell lung cancer (NSCLC) metastasis, driven by tumor-associated macrophages (TAMs), remains a significant challenge due to poor prognosis and limited therapeutic options. This study developed DSPE-PEG-M2pep-modified liposomal nanoparticles (M2pep-LNP@siITGB4) delivering siRNA targeting integrin β4 (siITGB4) to reprogram M2 TAMs and induce apoptosis in NSCLC cells, thereby inhibiting metastasis. Cationic liposomes were prepared using thin-film hydration and ultrasonic emulsification, with M2pep peptides enhancing targeted delivery to M2 macrophages. In vitro, THP-1-derived M2 macrophages were co-cultured with A549 and NCI-H1299 cells, and the effects on macrophage polarization and tumor cell behavior were assessed via RT-qPCR, Western blot, and Transwell assays. In vivo, A549 xenograft and lung metastasis models were analyzed using IVIS, flow cytometry, and RNA sequencing. M2pep-LNP@siITGB4 downregulated M2 markers (CD206, Arg1, IL-10), upregulated M1 markers (CD86, iNOS), and increased CD8 + T cell infiltration. Silencing ITGB4 reduced GNB5 expression and FAK/Src/AKT phosphorylation, promoting apoptosis and inhibiting epithelial-mesenchymal transition (EMT). RNA-seq revealed 3494 differentially expressed genes, with suppressed ECM-receptor interactions. Tumor volumes and metastatic lesions were significantly reduced. This approach effectively reprograms TAMs, induces tumor cell apoptosis, and suppresses NSCLC metastasis, offering a novel nanomedicine-based strategy for enhancing anti-tumor immunity and improving therapeutic outcomes in NSCLC.
