Heterochiral Assembly of Amphiphilic Peptides Inside the Mitochondria for Supramolecular Cancer Therapeutics

M. T. Jeena, Keunsoo Jeong, Eun Min Go, Yuri Cho, Seokyung Lee, Seongeon Jin, Suk Won Hwang, Joo Hee Jang, Chi Soo Kang, Woo Young Bang, Eunji Lee, Sang Kyu Kwak, Sehoon Kim, Ja Hyoung Ryu

    Research output: Contribution to journalArticlepeer-review

    73 Citations (Scopus)

    Abstract

    Self-assembly of peptides containing both l- and d-isomers often results in nanostructures with enhanced properties compared to their enantiomeric analogues, such as faster kinetics of formation, higher mechanical strength, and enzymatic stability. However, occurrence and consequences of the heterochiral assembly in the cellular microenvironment are unknown. In this study, we monitored heterochiral assembly of amphiphilic peptides inside the cell, specifically mitochondria of cancer cells, resulting in nanostructures with refined morphological and biological properties owing to the superior interaction between the backbones of opposite chirality. We have designed a mitochondria penetrating tripeptide containing a diphenyl alanine building unit, named as Mito-FF due to their mitochondria targeting ability. The short peptide amphiphile, Mito-FF co-assembled with its mirror pair, Mito-ff, induced superfibrils of around 100 nm in diameter and 0.5-1 μm in length, while enantiomers formed only narrow fibers of 10 nm in diameter. The co-administration of Mito-FF and Mito-ff in the cell induced drastic mitochondrial disruption both in vitro and in vivo. The experimental and theoretical analyses revealed that pyrene capping played a major role in inducing superfibril morphology upon the co-assembly of racemic peptides. This work shows the impact of chirality control over the peptide self-assembly inside the biological system, thus showing a potent strategy for fabricating promising peptide biomaterials by considering chirality as a design modality.

    Original languageEnglish
    Pages (from-to)11022-11033
    Number of pages12
    JournalACS nano
    Volume13
    Issue number10
    DOIs
    Publication statusPublished - 2019 Oct 22

    Bibliographical note

    Publisher Copyright:
    © 2019 American Chemical Society.

    Keywords

    • heterochiral assembly
    • intramitochondrial
    • self-assembly
    • supramolecular therapy

    ASJC Scopus subject areas

    • General Materials Science
    • General Engineering
    • General Physics and Astronomy

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