Wen Ping, Huang Hanwei, Zhang Ruizhe, Zheng Hanqi, Liang Tingxizi, Zhuang Chuyue, Wu Qing, Wang Junxia, Liu Feng, Zhang Ke, Wu Wei, He Kaixin, Liu Funan, Li Hongjun, Gu Zhen
State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China.
Nat Chem. 2025 Feb;17(2):279-288. doi: 10.1038/s41557-024-01705-8. Epub 2025 Jan 13.
Vesicles play critical roles in cellular materials storage and signal transportation, even in the formation of organelles and cells. Natural vesicles are composed of a lipid layer that forms a membrane for the enclosure of substances inside. Here we report a coacervate vesicle formed by the liquid-liquid phase separation of cholesterol-modified DNA and histones. Unlike a phospholipid-based membrane-bounded vesicle, a coacervate vesicle lacks a membrane structure on the surface and is organized with a high-density liquid layer and a water-filled cavity. Through a straightforward coacervation process, we demonstrate that various biological agents, including virus particles, mRNA, cytokines and peptides, can be innocuously and directly enriched in the liquid phase. In contrast to the droplet-like coacervates that are prone to aggregation challenges, coacervate vesicles display superior kinetic stability, positioning them as a versatile delivery vehicle for biopharmaceuticals. We validate that incorporating oncolytic viruses into these coacervate vesicles endows them with potent oncolytic efficacy and elicits robust anti-tumour immune responses in mouse models.
囊泡在细胞物质储存和信号运输中发挥着关键作用，甚至在细胞器和细胞的形成过程中也至关重要。天然囊泡由一层脂质构成，该脂质层形成了一个用于包裹内部物质的膜。在此，我们报道了一种由胆固醇修饰的DNA和组蛋白通过液-液相分离形成的凝聚囊泡。与基于磷脂的膜结合囊泡不同，凝聚囊泡表面缺乏膜结构，而是由一个高密度液体层和一个充满水的腔室组成。通过一个简单的凝聚过程，我们证明了包括病毒颗粒、mRNA、细胞因子和肽在内的各种生物制剂可以无害且直接地富集在液相中。与容易聚集的液滴状凝聚物不同，凝聚囊泡表现出卓越的动力学稳定性，使其成为生物制药的通用递送载体。我们验证了将溶瘤病毒纳入这些凝聚囊泡可赋予它们强大的溶瘤功效，并在小鼠模型中引发强烈的抗肿瘤免疫反应。
