State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, People's Republic of China; Medical Science and Technology Innovation Center, Shandong First Medical University, Jinan, Shandong 250117, People's Republic of China.
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, College of Biological Science and Medical Engineering, Donghua University, Shanghai 201620, People's Republic of China.
J Control Release. 2023 Jun;358:601-611. doi: 10.1016/j.jconrel.2023.05.021. Epub 2023 May 22.
Development of effective nanomedicines to deal with tumor immunogenicity and immunosuppression is vital to improve the immunotherapy efficacy. Herein, we developed a programmed strategy not only to activate the tumoral immune microenvironment through immunogenic cell death (ICD) effect but also to promote the maturation of dendritic cells (DCs) in lymph nodes through two modules of core-shell tecto dendrimer (CSTD)-based nanomedicines. The CSTDs with amplified tumor enhanced permeability and retention effect and improved gene delivery efficiency were formed by supramolecular self-assembly of generation 5 (G5) poly(amidoamine) dendrimers as cores and G3 dendrimers as shells. One module was employed to load doxorubicin for cancer cell chemotherapy to generate ICD, while the other module with partial surface modification of zwitterions and mannose was used for serum-enhanced YTHDF1 siRNA delivery to DCs to stimulate their maturation. These two modular CSTD-based nanomedicine formulations enable enhanced chemoimmunotherapy of an orthotopic breast tumor model through programmed treatment of cancer cells and DCs, and synergistic modulation of the maturation of DCs to activate the CD8/CD4 T cells for tumor killing. The developed CSTD-enabled nanomodules with improved drug/gene delivery performance may be applicable to tackle other cancer types via collaborative chemoimmunotherapy.
开发有效的纳米药物来应对肿瘤免疫原性和免疫抑制对于提高免疫疗法的疗效至关重要。在此，我们开发了一种程序化策略，不仅通过免疫原性细胞死亡（ICD）效应激活肿瘤免疫微环境，而且通过基于核壳结构的树枝状大分子（CSTD）纳米药物的两个模块促进淋巴结树突状细胞（DCs）的成熟。CSTD 由第 5 代（G5）聚（酰胺胺）树枝状大分子作为核和 G3 树枝状大分子作为壳通过超分子自组装形成，具有放大的肿瘤增强渗透和保留效应以及提高的基因传递效率。一个模块用于加载阿霉素进行癌细胞化疗以产生 ICD，而另一个模块则通过部分表面修饰两性离子和甘露糖用于血清增强 YTHDF1 siRNA 递送至 DCs 以刺激其成熟。这两种基于 CSTD 的模块化纳米药物制剂通过程序化治疗癌细胞和 DCs 实现了原位乳腺癌模型的增强化疗免疫治疗，并协同调节 DCs 的成熟以激活 CD8/CD4 T 细胞进行肿瘤杀伤。具有改进的药物/基因传递性能的开发 CSTD 使能的纳米模块可能适用于通过协同化疗免疫治疗来解决其他癌症类型。
