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Title: Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics
Authors: Sun, Yue
Lau, Sze Yi
Lim, Zhi Wei
Chang, Shi Chieh
Ghadessy, Farid
Partridge, Anthony
Miserez, Ali
Keywords: Science::Biological sciences
Issue Date: 2022
Source: Sun, Y., Lau, S. Y., Lim, Z. W., Chang, S. C., Ghadessy, F., Partridge, A. & Miserez, A. (2022). Phase-separating peptides for direct cytosolic delivery and redox-activated release of macromolecular therapeutics. Nature Chemistry, 14(3), 274-283.
Project: MOE 2019-T3-1-012
Journal: Nature Chemistry
Abstract: Biomacromolecules are highly promising therapeutic modalities to treat various diseases. However, they suffer from poor cellular membrane permeability, limiting their access to intracellular targets. Strategies to overcome this challenge often employ nanoscale carriers that can get trapped in endosomal compartments. Here we report conjugated peptides that form pH- and redox-responsive coacervate microdroplets by liquid-liquid phase separation that readily cross the cell membrane. A wide range of macromolecules can be quickly recruited within the microdroplets, including small peptides, enzymes as large as 430 kDa and messenger RNAs (mRNAs). The therapeutic-loaded coacervates bypass classical endocytic pathways to enter the cytosol, where they undergo glutathione-mediated release of payload, the bioactivity of which is retained in the cell, while mRNAs exhibit a high transfection efficiency. These peptide coacervates represent a promising platform for the intracellular delivery of a large palette of macromolecular therapeutics that have potential for treating various pathologies (for example, cancers and metabolic diseases) or as carriers for mRNA-based vaccines.
ISSN: 1755-4330
DOI: 10.1038/s41557-021-00854-4
Schools: School of Biological Sciences 
School of Materials Science and Engineering 
Research Centres: Biological and Biomimetic Material Laboratory (BBML)
Center for Sustainable Materials (SusMat)
Rights: © 2022 The Author(s), under exclusive licence to Springer Nature Limited. All rights reserved.
Fulltext Permission: none
Fulltext Availability: No Fulltext
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