M2pep-modified liposomal nanoparticles delivering siITGB4 induce apoptosis and inhibit NSCLC metastasis via
Xiaofeng Huang1, Fei Shen1, Dengshu Wang1
1Department of Cardiothoracic Surgery, Jiangyin Clinical College of Xuzhou Medical University, No. 163, Shoushan Road, Jiangyin, Wuxi, 214400, Jiangsu, China.
Abstract:
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.
Insights
This study developed novel nanoparticles to reprogram tumor-associated macrophages, reduce non-small cell lung cancer (NSCLC) metastasis, and enhance anti-tumor immunity. The findings offer a new nanomedicine strategy for improving NSCLC treatment outcomes.
Area of Science:
- Biomedical Engineering
- Nanomedicine
- Cancer Research
Background:
- Non-small cell lung cancer (NSCLC) metastasis is a major challenge, often driven by tumor-associated macrophages (TAMs).
- Current therapeutic options for NSCLC metastasis are limited, leading to poor patient prognosis.
Purpose of the Study:
- To develop targeted nanomedicine (M2pep-LNP@siITGB4) for reprogramming M2 TAMs and inhibiting NSCLC metastasis.
- To investigate the efficacy of siITGB4 delivery in suppressing tumor cell growth and inducing apoptosis.
Main Methods:
- Liposomal nanoparticles (M2pep-LNP@siITGB4) were prepared and characterized.
- In vitro studies assessed macrophage polarization and tumor cell behavior using co-cultures and molecular assays.
- In vivo efficacy was evaluated in NSCLC xenograft and metastasis models using imaging and omics analyses.
Main Results:
- M2pep-LNP@siITGB4 successfully reprogrammed M2 TAMs to an M1 phenotype, increasing CD8+ T cell infiltration.
- Silencing integrin β4 (ITGB4) inhibited epithelial-mesenchymal transition (EMT) and promoted apoptosis by downregulating GNB5 and FAK/Src/AKT signaling.
- Significant reduction in tumor volume and lung metastasis was observed, with suppressed ECM-receptor interactions.
Conclusions:
- The developed nanomedicine effectively reprograms TAMs and induces apoptosis in NSCLC cells, suppressing metastasis.
- This strategy enhances anti-tumor immunity and presents a promising nanomedicine-based approach for NSCLC therapy.
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