An Amphiphilic Cell‐Penetrating Macrocycle for Efficient Cytosolic Delivery of Proteins, DNA, and CRISPR Cas9

Author:

Qutub Somayah S.1,Bhat Imtiyaz Ahmad12,Maatouk Batoul I.1,Moosa Basem1,Fakim Aliyah1,Nawaz Kashif3,Diaz‐Galicia Escarlet4,Lin Weibin1,Grünberg Raik4,Arold Stefan T.4,Khashab Niveen M.1ORCID

Affiliation:

1. Smart Hybrid Materials (SHMs) Laboratory, Chemistry Program King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia

2. Current Address: Department of Chemistry Islamic University of Science and Technology Awantipora 192122, Jammu and Kashmir India

3. The Coral Symbiomics Lab, Red Sea Research Center King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia

4. Computational Bioscience Research Center (CBRC) King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia

Abstract

AbstractThe discovery of safe platforms that can circumvent the endocytic pathway is of great significance for biological therapeutics that are usually degraded during endocytosis. Here we show that a self‐assembled and dynamic macrocycle can passively diffuse through the cell membrane and deliver a broad range of biologics, including proteins, CRISPR Cas9, and ssDNA, directly to the cytosol while retaining their bioactivity. Cell‐penetrating macrocycle CPM can be easily prepared from the room temperature condensation of diketopyrrolopyrrole lactams with diamines. We attribute the high cellular permeability of CPM to its amphiphilic nature and chameleonic properties. It adopts conformations that partially bury polar groups and expose hydrophobic side chains, thus self‐assembling into micellar‐like structures. Its superior fluorescence makes CPM trackable inside cells where it follows the endomembrane system. CPM outperformed commercial reagents for biologics delivery and showed high RNA knockdown efficiency of CRISPR Cas9. We envisage that this macrocycle will be an ideal starting point to design and synthesize biomimetic macrocyclic tags that can readily facilitate the interaction and uptake of biomolecules and overcome endosomal digestion.

Publisher

Wiley

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