Targeting dual gene delivery nanoparticles overcomes immune checkpoint blockade induced adaptive resistance and regulates tumor microenvironment for improved tumor immunotherapy

• Published in: Nano today 2021-06, Vol.38, p.101194, Article 101194
• Main Authors: Feng, Yuanji, Wu, Jiayan, Chen, Jie, Lin, Lin, Zhang, Sijia, Yang, Zhiyu, Sun, Pingjie, Li, Yanhui, Tian, Huayu, Chen, Xuesi
• Format: Article
• Language: English
• Subjects: Adaptive resistance; Anti-tumor immunotherapy; Gene therapy; Tumor microenvironment; Tumor vessel normalization
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2021.101194

•A tumor targeting gene delivery system with high-efficiency was established to co-delivery pshVEGF-A and pshPD-L1.•Dual gene therapy overcame immune checkpoint blockade induced adaptive resistance.•Dual gene therapy reprogrammed tumor microenvironment to an immune-supportive profile through tumor vessel normalization.•Dual gene therapy provoked immune memory, leading to the inhibition of tumor recurrence and distant metastasis. [Display omitted] Despite the unparalleled tumor growth inhibition and significantly prolonged survival achieved by immune checkpoint blockade (ICB) therapy, more and more adaptive resistance to ICB therapy in clinical practice put patients at risk of uncontrollable tumor growth and tumor relapse. Hence, in this work, we constructed a targeting dual gene delivery system loading pshVEGF-A and pshPD-L1 against murine melanoma to overcome adaptive resistance for efficacious anti-tumor immunotherapy. We reported immune checkpoint blockade by PD-L1 gene silencing induced adaptive resistance through the VEGF-A/VEGF-R2 signal pathway. Therefore, the combination of PD-L1 and VEGF-A gene silencing eliminated adaptive resistance to ICB therapy. Besides, pshVEGF-A as an antiangiogenic agent achieved tumor vessel normalization and reprogramed tumor immune microenvironment towards an immune-supportive profile, synergizing with pshPD-L1 for significant tumor inhibition. This revolutionary dual gene therapy strategy contributed to the diversity of immune combination therapy and had a potential for clinical application in the near future.