Citation: Jianmian Fu, Shule Hou, Rui Huang, Bin Wang, Yuxuan Wu, Hui Dong, Jun Yang, Weiping Zhu, Yufang Xu, Penghui Chen, Jin Xie, Xuhong Qian, Yangyang Yang. Therapeutic coacervates for synergistic gene silencing and immune activation to treat solid tumors[J]. Chinese Chemical Letters, ;2026, 37(12): 112311. doi: 10.1016/j.cclet.2025.112311 shu

Therapeutic coacervates for synergistic gene silencing and immune activation to treat solid tumors

Jianmian Fu ^a ,
Shule Hou ^{b, c, d} ,
Rui Huang ^a ,
Bin Wang ^a ,
Yuxuan Wu ^{b, c, d} ,
Hui Dong ^{b, c, d, f} ,
Jun Yang ^{b, c, d} ,
Weiping Zhu ^a ,
Yufang Xu ^a ,
Penghui Chen ^{b, c, d, *,} ,
Jin Xie ^{b, c, d, *,} ,
Xuhong Qian ^{a, e, *,} ,
Yangyang Yang ^{a, *,}

a.
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b.
Department of Otorhinolaryngology-Head and Neck Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
c.
Ear Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
d.
Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Shanghai 200092, China
e.
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
f.
Department of Otorhinolaryngology-Head and Neck Surgery, Yantaishan Hospital, Yantaishan Hospital Affiliated to Binzhou Medical University, Yantai 264000, China

Received Date: 17 October 2025
Revised Date: 20 December 2025
Accepted Date: 22 December 2025
Available Online: 22 December 2025

Figures(4)

Single-modality cancer therapies face limitations from tumor heterogeneity, drug resistance, and immune evasion. Combination therapies, particularly those that merge nucleic acid-based and immune-based therapeutics, offer promise by leveraging synergy; however, both face delivery challenges. This study reports a liquid-liquid phase separation (LLPS)-driven therapeutic coacervate system designed to simultaneously deliver nucleic acid drugs and immunostimulators for synergistic antitumor treatment. Short elastin-like polypeptide-antisense oligonucleotide (E-ASO) conjugates are synthesized to form membraneless coacervates via LLPS. These E-ASO coacervates directly internalize into cells and potently silence anti-apoptotic gene, Bcl-2, across six distinct cancer cell lines. By incorporating the stimulator of interferon gene (STING) agonist cyclic GMP-AMP (cGAMP), E-ASO-cGAMP coacervates are generated, which simultaneously downregulate Bcl-2 and activate the STING pathway, triggering cytokine production and immune activation. In melanoma and hypopharyngeal carcinoma mouse models, E-ASO-cGAMP coacervates demonstrate significantly enhanced antitumor efficacy compared to monotherapies, with potent and consistent tumor suppression across both immunologically distinct tumor types. The platform shows no observable systemic toxicity in vital organs. This LLPS-driven coacervate system establishes a new model for combined anticancer therapy, overcoming delivery barriers to synergistically integrate gene silencing and immune activation and provide a translatable strategy for solid tumor treatment.
- Liquid-liquid phase separation,
- Antisense oligonucleotide,
- Immune therapy,
- Nucleic acid therapy,
- Gene silencing
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