In situ formation of biomolecular condensates as intracellular drug reservoirs for augmenting chemotherapy

Tingxizi Liang; Yuxiang Dong; Irina Cheng; Ping Wen; Fengqin Li; Feng Liu; Qing Wu; En Ren; Peifeng Liu; Hongjun Li; Zhen Gu

doi:10.1038/s41551-024-01254-y

In situ formation of biomolecular condensates as intracellular drug reservoirs for augmenting chemotherapy

Nat Biomed Eng. 2024 Sep 13. doi: 10.1038/s41551-024-01254-y. Online ahead of print.

Authors

Tingxizi Liang^#¹, Yuxiang Dong^#², Irina Cheng¹, Ping Wen¹, Fengqin Li³, Feng Liu¹, Qing Wu¹, En Ren¹, Peifeng Liu⁴, Hongjun Li^{5

6}, Zhen Gu^{7

8

9

10}

Affiliations

¹ State Key Laboratory of Advanced Drug Delivery and Release Systems, and Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
² School of Materials Science and Engineering, Suzhou University of Science and Technology, Suzhou, China.
³ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. [email protected].
⁵ State Key Laboratory of Advanced Drug Delivery and Release Systems, and Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
⁶ Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
⁷ State Key Laboratory of Advanced Drug Delivery and Release Systems, and Liangzhu Laboratory, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. [email protected].
⁸ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
⁹ Jinhua Institute of Zhejiang University, Jinhua, China. [email protected].
¹⁰ MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China. [email protected].

^# Contributed equally.

PMID: 39271933
DOI: 10.1038/s41551-024-01254-y

Abstract

Biomolecular condensates, which arise from liquid-liquid phase separation within cells, may provide a means of enriching and prolonging the retention of small-molecule drugs within cells. Here we report a method for the controlled in situ formation of biomolecular condensates as reservoirs for the enrichment and retention of chemotherapeutics in cancer cells, and show that the approach can be leveraged to enhance antitumour efficacies in mice with drug-resistant tumours. The method involves histones as positively charged proteins and doxorubicin-intercalated DNA strands bioorthogonally linked via a click-to-release reaction between trans-cyclooctene and tetrazine groups. The reaction temporarily impaired the phase separation of histones in vitro, favoured the initiation of liquid-liquid phase separation within cells and led to the formation of biomolecular condensates that were sufficiently large to be retained within tumour cells. The controlled formation of biomolecular condensates as drug reservoirs within cells may offer new options for boosting the efficacies of cancer therapies.