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Multifunctional Biomimetic Nanocarriers for Dual-Targeted Immuno-Gene Therapy Against Hepatocellular Carcinoma
Yupeng Sun1,2, Yan Liu1,3, Rui Li1,3
1The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, P. R. China.
Abstract:
Growing evidences have proved that tumors evade recognition and attack by the immune system through immune escape mechanisms, and PDL1/Pbrm1 genes have a strong correlation with poor response or resistance to immune checkpoint blockade (ICB) therapy. Herein, a multifunctional biomimetic nanocarrier (siRNA-CaP@PD1-NVs) is developed, which can not only enhance the cytotoxic activity of immune cells by blocking PD1/PDL1 axis, but also reduce tumor immune escape via Pbrm1/PDL1 gene silencing, leading to a significant improvement in tumor immunosuppressive microenvironment. Consequently, the nanocarrier promotes DC cell maturation, enhances the infiltration and activity of CD8+ T cells, and forms long-term immune memory, which can effectively inhibit tumor growth or even eliminate tumors, and prevent tumor recurrence and metastasis. Overall, this study presents a powerful strategy for co-delivery of siRNA drugs, immune adjuvant, and immune checkpoint inhibitors, and holds great promise for improving the effectiveness and safety of current immunotherapy regimens.
Insights
This study developed a nanocarrier to block PD1/PDL1 and silence Pbrm1/PDL1 genes, enhancing anti-tumor immunity. This approach improves the tumor microenvironment, inhibits tumor growth, and prevents recurrence.
Area of Science:
- Biomedical Engineering
- Immunology
- Nanotechnology
Background:
- Tumors employ immune escape mechanisms, hindering effective anti-cancer immunity.
- The PDL1/Pbrm1 gene axis is linked to poor response to immune checkpoint blockade (ICB) therapy.
Purpose of the Study:
- To develop a multifunctional nanocarrier for combined gene silencing and immune checkpoint inhibition.
- To enhance anti-tumor immune responses and overcome tumor immune escape.
Main Methods:
- A biomimetic nanocarrier (siRNA-CaP@PD1-NVs) was engineered for co-delivery.
- The nanocarrier targets PD1/PDL1 axis blockade and Pbrm1/PDL1 gene silencing.
Main Results:
- The nanocarrier significantly improved the tumor immunosuppressive microenvironment.
- Enhanced dendritic cell (DC) maturation, CD8+ T cell infiltration, and activity were observed.
- Effective tumor growth inhibition, prevention of recurrence, and metastasis were achieved.
Conclusions:
- The developed nanocarrier offers a potent strategy for co-delivery of siRNA, immune adjuvants, and ICB agents.
- This approach holds significant promise for improving immunotherapy effectiveness and safety.
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