Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals

Ping Wen^#¹, Hanwei Huang^#^{2

3

4}, Ruizhe Zhang^{2

3

4}, Hanqi Zheng¹, Tingxizi Liang¹, Chuyue Zhuang¹, Qing Wu¹, Junxia Wang¹, Feng Liu¹, Ke Zhang¹, Wei Wu⁵, Kaixin He¹, Funan Liu^{6

7

8}, Hongjun Li^{9

10}, Zhen Gu^{11

12

13

14}

Affiliations

¹ State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China.
³ Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, China Medical University, Ministry of Education, Shenyang, China.
⁴ Phase I Clinical Trials Center, The First Hospital, China Medical University, Shenyang, China.
⁵ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁶ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China. fnliu@cmu.edu.cn.
⁷ Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, China Medical University, Ministry of Education, Shenyang, China. fnliu@cmu.edu.cn.
⁸ Phase I Clinical Trials Center, The First Hospital, China Medical University, Shenyang, China. fnliu@cmu.edu.cn.
⁹ State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹⁰ Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹¹ State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹² Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹³ Jinhua Institute of Zhejiang University, Jinhua, China. guzhen@zju.edu.cn.
¹⁴ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.

^# Contributed equally.

PMID: 39806140
DOI: 10.1038/s41557-024-01705-8

Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals

Ping Wen et al. Nat Chem. 2025 Feb.

. 2025 Feb;17(2):279-288.

doi: 10.1038/s41557-024-01705-8. Epub 2025 Jan 13.

Authors

Affiliations

¹ State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China.
³ Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, China Medical University, Ministry of Education, Shenyang, China.
⁴ Phase I Clinical Trials Center, The First Hospital, China Medical University, Shenyang, China.
⁵ Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁶ Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China. fnliu@cmu.edu.cn.
⁷ Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumours, China Medical University, Ministry of Education, Shenyang, China. fnliu@cmu.edu.cn.
⁸ Phase I Clinical Trials Center, The First Hospital, China Medical University, Shenyang, China. fnliu@cmu.edu.cn.
⁹ State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹⁰ Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. hongjun@zju.edu.cn.
¹¹ State Key Laboratory of Advanced Drug Delivery and Release Systems, Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹² Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.
¹³ Jinhua Institute of Zhejiang University, Jinhua, China. guzhen@zju.edu.cn.
¹⁴ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. guzhen@zju.edu.cn.

^# Contributed equally.

PMID: 39806140
DOI: 10.1038/s41557-024-01705-8

Abstract

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.

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Conflict of interest statement

Competing interests: The patent applications related to this work have been filed in China by Z.G., H.L. and P.W. (application nos. PCT/CN2023/092187, 2023104903783). Z.G. is the co-founder of Zenomics Inc., Zcapsule Inc. and μZen Inc. The other authors declare no competing interests.

References

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Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals

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Coacervate vesicles assembled by liquid-liquid phase separation improve delivery of biopharmaceuticals

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