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한국과학기술연구원(KIST), 한양대학교

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Adv. Mater., Oct 18 2025, | https://doi.org/10.1002/adma.202507877 Intrinsically Disordered Protein-Inspired Nanovector-Based Coacervates for the Direct Cytosolic Transport of Biomacromolecules

Soyeong Jin^{1 2 †}, Hyemin Park ^{1 3 †}, Seuk-Min Ryu ^{1 †}, Dagyeong Guk ^{1 3}, Jaeeun Lee ⁴, Seongeon Jin ¹, Changjoon Keum ¹, Jinyoung Park ^{1 5}, Myoung-Hwan Park ⁶, Chaekyu Kim ⁷, Hojun Kim ^{1 5}, Jaegeun Noh ^{2 8}, Kwan Hyi Lee ^{1 3 5 *}, Ja-Hyoung Ryu ^{4 *}, Youngdo Jeong ^{1 5 9 *}

¹Center for Advanced Biomolecular Recognition, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
²Department of Chemistry, Hanyang University, Seoul, 04763, Republic of Korea.
³KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea.
⁴Department of Chemistry, College of Natural Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea.
⁵Division of Biomedical Science & Technology, University of Science and Technology, Daejeon, 34113, Republic of Korea.
⁶Department of Chemistry and Life Science, Sahmyook University, Seoul, 01795, Republic of Korea.
⁷Fusion Biotechnology, Inc., Ulsan, 44919, Republic of Korea.
⁸Research Institute for Convergence of Basic Science, Hanyang University, Seoul, 04763, Republic of Korea.
⁹Department of HY-KIST BioConvergence, Hanyang University, Seoul, 04763, Republic of Korea.

^†S.J., H.P., and S.-M.R. contributed equally to this work.

^*Corresponding authors: correspondence to Kwan Hyi Lee, Ja-Hyoung Ryu or Youngdo Jeong

Abstract

In eukaryotic cells, membraneless organelles (MLOs) are formed via liquid‒liquid phase separation (LLPS) involving intrinsically disordered proteins (IDPs) and biomacromolecules, enabling biomacromolecule transport without vesicles, transporters, or channels. Although MLO-mimetic coacervates generated from synthetic biomaterials can deliver biomacromolecules into cells, they lack the conformational adaptability of IDPs and a defined internalization mechanism, limiting their stability under physiological conditions and hindering biomedical translation. Here, IDP-inspired nanovectors (IDP-NVs) are developed with conformational adaptability capable of forming nanocoacervates (NCs) with biomacromolecules for cytosolic delivery. Mixing with IDP-NVs and cargos results in stable NCs under physiological conditions, and the NCs can directly penetrate cellular membranes through the molecular motion of IDP-NVs. After the internalization, cytoplasmic glutathione triggers NC disassembly, releasing biomacromolecules in the cytosol. The NCs effectively deliver biomacromolecules of diverse sizes, charges, shapes (globular proteins and antibodies), and functions (mRNAs and CRISPR units), demonstrating their versatility and potential for biomedical applications.

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