Xing Yumeng, Wu Ruiying, Tu Zhaoyuan, Meng Meng, Xiang Longwei, Li Huixin, Shi Zongwei, Fang Guanhe, Feng Yuanji, Li Ziqin, Tian Huayu, Chen Xuesi
State Key Laboratory of Physical Chemistry of Solid Surfaces, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, 361005, China.
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China; School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China.
Biomaterials. 2026 Jan;324:123527. doi: 10.1016/j.biomaterials.2025.123527. Epub 2025 Jun 25.
Cancer vaccines have demonstrated their potential in cancer immunotherapy. However, various agonists in free form are easily to be eliminated in vivo and may cause systemic adverse effects. It remains a challenge to effectively target and release agonists at their receptor locations and prevent undesirable leakage. Herein, we present a dual-responsive nanovaccine (DRNV) for targeted delivery of toll-like receptor (TLR) agonists. DRNV was formed by self-assembly of antigen and degradable amphiphilic polymer, polyethylene glycol modified poly (lipoic acid) (PTA). Imidazoquinoline (IMDQ), a classical TLR7/8 agonist, was covalently conjugated to PTA with an enzyme-responsive linker. With this design, DRNV can avoid rapid elimination and potential toxicity due to systemic diffusion. Furthermore, the PTA core would be quickly degraded in response to intracellular glutathione, leading to the disintegration of DRNV and promoting enzyme-responsive release of IMDQ, ultimately stimulating TLR7/8 receptors on the inner membrane of endosomes. Systemic animal experiments demonstrated that DRNV effectively inhibits tumor growth and triggers protective antitumor immune responses to against tumor rechallenge and metastasis. Overall, this work demonstrates a feasible nanoplatform for the precise delivery of TLR agonists and tumor antigens, providing insights into the design of advanced nanovaccine for effective and safe cancer immunotherapy.
癌症疫苗已在癌症免疫治疗中展现出其潜力。然而，游离形式的各种激动剂在体内易于被清除，且可能会引起全身不良反应。在受体位置有效靶向并释放激动剂，同时防止不必要的泄漏，仍然是一项挑战。在此，我们提出一种用于靶向递送 Toll 样受体（TLR）激动剂的双响应纳米疫苗（DRNV）。DRNV 由抗原和可降解两亲聚合物聚乙二醇修饰的聚（硫辛酸）（PTA）自组装形成。经典的 TLR7/8 激动剂咪唑喹啉（IMDQ）通过酶响应连接子与 PTA 共价连接。通过这种设计，DRNV 可避免因全身扩散导致的快速清除和潜在毒性。此外，PTA 核心会响应细胞内谷胱甘肽而迅速降解，导致 DRNV 解体并促进 IMDQ 的酶响应释放，最终刺激内体内膜上的 TLR7/8 受体。全身动物实验表明，DRNV 能有效抑制肿瘤生长，并触发保护性抗肿瘤免疫反应以抵抗肿瘤再次攻击和转移。总体而言，这项工作展示了一种用于精确递送 TLR 激动剂和肿瘤抗原的可行纳米平台，为设计有效且安全的癌症免疫治疗高级纳米疫苗提供了思路。
