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Updated: Sep 16, 2025

Direct Protein Delivery to Mammalian Cells Using Cell-permeable Cys2-His2 Zinc-finger Domains
Published on: March 25, 2015
Breaking the cellular delivery bottleneck: recent developments in direct cytosolic delivery of biologics
Harini Nagaraj1, Victor Lehot1, Nourina Nasim1
1Department of Chemistry, University of Massachusetts Amherst 710 North Pleasant Street Amherst Massachusetts 01003 USA rotello@chem.umass.edu.
Abstract:
Proteins and nucleic acid therapeutics represent a significant and growing share of the pharmaceutical landscape. The majority of biological and therapeutic applications of these biomolecules require access to the cytosol. Delivery of biologics directly to the cytosol is made difficult by the impermeability of the cell membrane. As a result, most delivery strategies have utilized endocytic uptake pathways to deliver biologics into the cell. However, endosomally entrapped cargo often faces limited escape efficiency and is prone to degradation within endo/lysosomal compartments. The emergence of delivery vehicles capable of bypassing endocytosis and directly traversing the cell membrane offers a promising approach to improve the cytosolic delivery efficiency of biomolecules. Here, we highlight recent developments in endocytosis-independent delivery systems for biologics and ways to accurately assess cytosolic delivery of biologics. Strategies employing covalent and non-covalent modification of biomolecules will be reviewed, along with strategies incorporating both covalent and supramolecular processes.
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