Curcumin coacervates for supramolecular-interaction responsive cytosolic siRNA delivery to enhance pyroptosis

Sep 30, 2026

Uploaded by Miles

Synthetic “sticker-and-spacer” molecules often form coacervates through liquid-liquid phase separation, creating functions distinct from soluble forms, but natural compounds are not well established to do so. Curcumin is shown to produce phase-separated fluorescent coacervates upon dilution into water, enabling encapsulation and transport of proteins and nucleic acids into cells. β-cyclodextrin disrupts the coacervates via supramolecular interactions for cytosolic cargo release, enhancing tumor accumulation and anticancer efficacy with siRNA in vivo.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Abstract

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Methods

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Introduction

Theranostics 2026, Vol. 16, Issue 6 2705 Ivyspring International Publisher Theranostics 2026; 16(6): 2705-2720. doi: 10.7150/thno.121865 Research Paper Curcumin coacervates for supramolecular-interactionresponsive cytosolic siRNA delivery to enhance pyroptosis Kai Cheng1†, Fang Zhang2†, Yishu Bao1, Zhiyi Xu1, Hao Kong1, Dingdong Yuan1, Zhong Zheng1, Yuan-Di Zhao2􀀍, Jiang Xia1􀀍 1. Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, P. R. China. 2. Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China. † K. C. and F. Z. contributed equally. 􀀍 Corresponding authors: [zydi@mail.hust.edu.cn](zydi@mail.hust.edu.cn) (Y.D. Zhao); [jiangxia@cuhk.edu.hk](jiangxia@cuhk.edu.hk) ORCID 0000-0001-8112-7625; Phone: (852) 3943 6165; Fax: (852) 2603 5057. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.07.17; Accepted: 2025.11.05; Published: 2026.01.01 Abstract Rationale: Synthetic molecules, meticulously designed according to the “sticker-and-spacer model”, tend to form coacervates via liquid-liquid phase separation (LLPS), thereby acquiring properties beyond their discrete and soluble states. However, natural compounds, such as those from traditional Chinese medicines (TCMs), are not known to undergo phase separation. In this study, we demonstrate that curcumin, the active ingredient in the spice turmeric, forms phase-separated fluorescent coacervates when diluted from a concentrated organic-solvent solution into an aqueous solution. Methods: Curcumin coacervates were formed by diluting a concentrated stock solution in organic solvents into the aqueous solution. We utilized the coacervate droplets to encapsulate and transport various biomacromolecules, such as proteins and nucleic acids, across the plasma membrane into the cell. Supramolecular interaction between β-cyclodextrin (β-CD) and curcumin disassembles curcumin coacervates, leading to cargo release in the cytosol. Results: Intravenously injected curcumin coacervates spontaneously enrich in the tumor tissue in tumor-bearing BALB/cmice. Subsequent intratumoral injection of β-CD significantly enhances anticancer effects in mice, demonstrating the efficacy of coacervate-mediated siRNA drug delivery and supramolecular-interaction-responsive intracellular release in vivo. Conclusions: Taken together, we report here the coacervate-forming properties of the natural TCM compound curcumin, presenting a unique strategy for controlling coacervate states through supramolecular interactions with β-cyclodextrin in vitro and in vivo, along with the unexplored potential of curcumin coacervate-mediated siRNA delivery to enhance pyroptosis. Keywords: curcumin coacervates, supramolecular interaction, cyclodextrin-responsive release, cytosolic delivery, enhanced pyroptosis Introduction Liquid-liquid phase separation (LLPS) describes a physical phenomenon where molecules form highly concentrated liquid condensates in an aqueous solution, driven by weak interactions between molecules such as hydrogen bonds, electrostatic forces, and hydrophobic interactions, etc. [1-4] . These condensates are separated from the bulk solution by a well-defined boundary, across which concentrations of the two phases differ by several orders of magnitude. Yet, molecules in the condensed phase and the dilute phase dynamically exchange. Initially recognized as a common occurrence in polymer solutions, LLPS of biopolymers has recent

FAQs

How are curcumin coacervates formed in this study?

Curcumin coacervates are generated by diluting a concentrated organic-solvent stock solution into an aqueous solution, producing phase-separated fluorescent droplets.

What role does β-cyclodextrin play in the system?

β-cyclodextrin interacts supramolecularly with curcumin to disassemble the coacervates, triggering cargo release in the cytosol.

How does the approach affect tumor targeting and therapeutic outcomes?

Intravenously injected curcumin coacervates enrich in tumor tissue, and subsequent intratumoral β-cyclodextrin injection significantly enhances anticancer effects, demonstrating effective siRNA delivery and intracellular release in vivo.

Sep 30, 2026

Uploaded by Miles