Chemically modified CRISPR enzymes for multi-organ genome editing in vivo
- 1Innovative Genomics Institute, Berkeley, United States & University of California-Berkeley, Berkeley, United States
Abstract
Delivery remains the main obstacle to the development of in vivo genome editing therapies. CRISPR ribonucleoproteins confer high editing activity with transient exposure but lack intrinsic cell entry and targeting. Here we introduce PERCEPT, a delivery platform featuring reversible, covalent modification of CRISPR enzymes. PERCEPT enables modular installation of shielding polymers, amphiphilic delivery peptides and targeting ligands, allowing traceless cytosolic release of the native editor. A formulation incorporating an amphiphilic delivery peptide and the neuron-targeting ligand TET1 edited approximately 56% of striatal volume and 78% of neurons within edited regions after local striatal administration. In the R6/2 Huntington's disease model, PERCEPT mediated targeted editing of the mutant human HTT transgene, reducing mutant huntingtin aggregate burden and shifting local transcriptional programs away from inflammatory and injury-associated states. Tissue-adapted formulations edited 53% of Muller glia following intravitreal delivery, increased skeletal muscle reporter fluorescence tenfold versus unconjugated control following intramuscular injection, and enabled lung airway epithelial cell that persisted for three months following intranasal delivery. Rapid screening revealed that local anatomical and cellular barriers require distinct surface display for optimal editing. These results establish reversible chemical modification as a general strategy for adapting CRISPR enzyme delivery across multiple target tissues in vivo.
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BibTeX
@misc{baehr2026chemically,
title = {{Chemically modified CRISPR enzymes for multi-organ genome editing in vivo}},
author = {C. M. Baehr and A. Ressnerova and M. Kang and S. Zhao and B. Le and R. F. Haddad and K. Asija and M. Damate and R. Sharma and C. George and H. Huang and D. Assa and E. A. Noel and B. Manohar and P. A. Otero and M. Travis and K. Saikaly and S. Hu and V. S. Van Laar and R. R. Lonser and J. G. Flannery and N. Murthy and R. C. Wilson},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751351},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751351v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Chemically modified CRISPR enzymes for multi-organ genome editing in vivo
AU - C. M. Baehr
AU - A. Ressnerova
AU - M. Kang
AU - S. Zhao
AU - B. Le
AU - R. F. Haddad
AU - K. Asija
AU - M. Damate
AU - R. Sharma
AU - C. George
AU - H. Huang
AU - D. Assa
AU - E. A. Noel
AU - B. Manohar
AU - P. A. Otero
AU - M. Travis
AU - K. Saikaly
AU - S. Hu
AU - V. S. Van Laar
AU - R. R. Lonser
AU - J. G. Flannery
AU - N. Murthy
AU - R. C. Wilson
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751351
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751351v1
AB - Delivery remains the main obstacle to the development of in vivo genome editing therapies. CRISPR ribonucleoproteins confer high editing activity with transient exposure but lack intrinsic cell entry and targeting. Here we introduce PERCEPT, a delivery platform featuring reversible, covalent modification of CRISPR enzymes. PERCEPT enables modular installation of shielding polymers, amphiphilic delivery peptides and targeting ligands, allowing traceless cytosolic release of the native editor. A formulation incorporating an amphiphilic delivery peptide and the neuron-targeting ligand TET1 edited approximately 56% of striatal volume and 78% of neurons within edited regions after local striatal administration. In the R6/2 Huntington's disease model, PERCEPT mediated targeted editing of the mutant human HTT transgene, reducing mutant huntingtin aggregate burden and shifting local transcriptional programs away from inflammatory and injury-associated states. Tissue-adapted formulations edited 53% of Muller glia following intravitreal delivery, increased skeletal muscle reporter fluorescence tenfold versus unconjugated control following intramuscular injection, and enabled lung airway epithelial cell that persisted for three months following intranasal delivery. Rapid screening revealed that local anatomical and cellular barriers require distinct surface display for optimal editing. These results establish reversible chemical modification as a general strategy for adapting CRISPR enzyme delivery across multiple target tissues in vivo.
ER -