2. Academic Validation
  3. Phase-separating peptide coacervates with programmable material properties for universal intracellular delivery of macromolecules

Phase-separating peptide coacervates with programmable material properties for universal intracellular delivery of macromolecules

  • Nat Commun. 2024 Nov 21;15(1):10094. doi: 10.1038/s41467-024-54463-z.
Yue Sun 1,  Xi Wu 1,  Jianguo Li 2 3,  Milad Radiom 4,  Raffaele Mezzenga 1 4 5,  Chandra Shekhar Verma 2 6 7,  Jing Yu 1 8,  Ali Miserez 9 10
Affiliations

Affiliations

  • 1 Center for Sustainable Materials (SusMat), School of Materials Science and Engineering, Nanyang Technological University, 639798, Singapore, Singapore.
  • 2 Bioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, Matrix, 138671, Singapore, Singapore.
  • 3 Singapore Eye Research Institute, 169856, Singapore, Singapore.
  • 4 Department of Health Sciences & Technology, ETH Zurich, 8092, Zürich, Switzerland.
  • 5 Department of Materials, ETH Zurich, 8092, Zürich, Switzerland.
  • 6 Department of Biological Sciences, National University of Singapore, 117558, Singapore, Singapore.
  • 7 School of Biological Sciences, Nanyang Technological University, 637551, Singapore, Singapore.
  • 8 Institute for Digital Molecular Analytics and Science, Nanyang Technological University, 636921, Singapore, Singapore.
  • 9 Center for Sustainable Materials (SusMat), School of Materials Science and Engineering, Nanyang Technological University, 639798, Singapore, Singapore. ali.miserez@ntu.edu.sg.
  • 10 School of Biological Sciences, Nanyang Technological University, 637551, Singapore, Singapore. ali.miserez@ntu.edu.sg.
PMID: 39572548 DOI: 10.1038/s41467-024-54463-z
Abstract

Phase-separating Peptides (PSPs) self-assembling into coacervate microdroplets (CMs) are a promising class of intracellular delivery vehicles that can release macromolecular modalities deployed in a wide range of therapeutic treatments. However, the molecular grammar governing intracellular uptake and release kinetics of CMs remains elusive. Here, we systematically manipulate the sequence of PSPs to unravel the relationships between their molecular structure, the physical properties of the resulting CMs, and their delivery efficacy. We show that a few amino acid alterations are sufficient to modulate the viscoelastic properties of CMs towards either a gel-like or a liquid-like state as well as their binding interaction with cellular membranes, collectively enabling to tune the kinetics of intracellular cargo release. We also demonstrate that the optimized PSPs CMs display excellent transfection efficiency in hard-to-transfect cells such as primary fibroblasts and immune cells. Our findings provide molecular guidelines to precisely program the material properties of PSP CMs and achieve tunable cellular uptake and release kinetics depending on the cargo modality, with broad implications for therapeutic applications such as protein, gene, and immune cell therapies.

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