Issue 22, 2023

Liquid–liquid phase separation for microencapsulation of native cytokine to enhance immune activation

Abstract

Therapeutic cytokines have achieved remarkable success in combination immunotherapy against malignant tumors. Nonetheless, their short half-life in the bloodstream leads to poor compliance and hinders their clinical effectiveness. While some pegylated cytokines have been developed to extend their circulation half-life, structural modifications often alter cytokines’ receptor affinities, reduce their activity, and even pose the risk of reversing their clinical effects. Therefore, there is an urgent need to develop new long-acting cytokines with stable blood concentration profiles and high activity. Inspired by the biomimetic partition process of liquid–liquid phase separation (LLPS) in living cells, we designed a method for microencapsulating cytokines into polymer microparticles driven by LLPS, enabling sustained delivery of native cytokines with high activity. Initially, we created a PEG/dextran aqueous biphasic system by mixing porous microparticles loaded with dextran-70 kDa and a PEG-20 kDa solution. Next, we introduced GM-CSF as a model cytokine into the biphasic system, allowing it to be distributed into the dextran-rich phase under the driving force of LLPS. We then sealed the porous microparticles to complete the microencapsulation of GM-CSF, resulting in GM-CSF/LLPS-MP. GM-CSF/LLPS-MP demonstrated a consistent release of native GM-CSF over a two-week period, promoting dendritic cell differentiation and function. Moreover, it enhanced the synergistic inhibitory effect of GM-CSF and PD-1 antibodies on melanoma tumors compared to GM-CSF solution. These findings offer proof of concept that liquid–liquid phase separation is an effective method for achieving the microencapsulation of native cytokines, thereby enhancing immune activation.

Graphical abstract: Liquid–liquid phase separation for microencapsulation of native cytokine to enhance immune activation

Supplementary files

Article information

Article type
Paper
Submitted
13 Jul 2023
Accepted
20 Oct 2023
First published
20 Oct 2023
This article is Open Access
Creative Commons BY-NC license

Mater. Adv., 2023,4, 5643-5652

Liquid–liquid phase separation for microencapsulation of native cytokine to enhance immune activation

Z. Hu, L. Cheng, Q. Chen, T. Xin and X. Wu, Mater. Adv., 2023, 4, 5643 DOI: 10.1039/D3MA00405H

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