Highly efficient and long-acting split-and-mix proteolysis targeting chimera based on self-assembled polylactic acid

Mei-miao Zhan, Hailing Chen, Meiling He, Chunli Song, Zijun Jiao, Na Liu, Zhihong Liu, Zhanfeng Hou, Ying Chen, Zhibo Song, Yun Xing, Zigang Li () and Feng Yin ()
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Mei-miao Zhan: Shenzhen Bay Laboratory, Pingshan Translational Medicine Center
Hailing Chen: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Meiling He: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Chunli Song: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Zijun Jiao: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Na Liu: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Zhihong Liu: Shenzhen Bay Laboratory, Pingshan Translational Medicine Center
Zhanfeng Hou: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Ying Chen: Shenzhen Bay Laboratory, Pingshan Translational Medicine Center
Zhibo Song: Peking University Shenzhen Graduate School, School of Advanced Material
Yun Xing: Peking University Shenzhen Graduate School, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology
Zigang Li: Shenzhen Bay Laboratory, Pingshan Translational Medicine Center
Feng Yin: Shenzhen Bay Laboratory, Pingshan Translational Medicine Center

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Proteolysis targeting chimera (PROTAC) technology has received extensive attention due to its “event-driven” mechanism of action. However, existing chimera molecules tend to have higher molecular weight and higher polar surface area and exhibit lower druggable properties. In order to effectively improve the bioavailability, circulation time and other proprietary drug parameters of “chimera molecules”, we combine the characteristics of nanotechnology and chimera technology, and propose the strategy of “Split-and-Mix” proteolysis degradation (SM-PROTAC) technology. However, both peptide- and liposome-based SM-PROTAC showed suboptimal in vivo efficiency. Hence, in this study, we incorporated Polylactic acid (PLA), an FDA-approved biomedical material, as the self-assembled matrix for SM-PROTAC to enhance in vivo effectiveness. PLA-based SM-PROTACs successfully degrade model targets including BRD4, ERα, and CDK4 in cellular assays and display more obvious tumor inhibition in vivo in female mice with a lower target ligand content (~1/10 of small molecule PROTAC controls) and long-term therapeutic potential (1 injection per three days vs 1 injection every day). In summary, PLA-based SM-PROTACs demonstrate promising drug characteristics and present obvious advantages in low-dose and long-term applications, providing additional insights into the pharmaceutical potential of the SM-PROTAC strategy.

Date: 2025
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DOI: 10.1038/s41467-025-65590-6

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