Peptide Therapeutics|Advanced4 min

How Cell-Penetrating Peptides Deliver CRISPR

Watch a cell-penetrating peptide carry a CRISPR-Cas9 ribonucleoprotein across a cell membrane and into the nucleus. The flagship explainer tying peptides to gene editing.

How Cell-Penetrating Peptides Deliver CRISPR

TAT, poly-arginine & the non-viral path into the cell

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The Cargo: CRISPR RNP

A Cas9 protein + sgRNA complex

The cargo we want to deliver is a ribonucleoprotein (RNP) — the Cas9 protein pre-loaded with its single guide RNA. RNP delivery is attractive because editing happens fast and the Cas9 degrades within ~24–72 hours, reducing off-target edits compared with plasmid or mRNA.

The problem: Cas9 is large (~160 kDa), highly negatively charged from the bound sgRNA, and biologically it has no way to cross a cell membrane.

Traditional delivery routes like AAV or lipid nanoparticles have limits — AAV has a ~4.7 kb cargo cap, and LNPs tend to accumulate in the liver. A method that could carry an RNP across any membrane would unlock new editing strategies.

Key Point

Cas9 RNPs are the cleanest form of CRISPR — but you still need a way to smuggle a 160 kDa negatively charged complex across a lipid bilayer.

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What You'll Learn

1Why CRISPR-Cas9 can't cross cell membranes on its own
2How cationic peptides like TAT and poly-arginine enable translocation
3The direct translocation vs endocytic uptake pathways
4Why CPPs could solve problems that AAV and LNP delivery can't

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