Plasma membrane damage limits cytoplasmic delivery by conventional cell penetrating peptides.

Autor: Polderdijk SGI; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, United States of America., Limzerwala JF; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, United States of America., Spiess C; Department of Antibody Engineering, Genentech Inc., South San Francisco, CA, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2024 Sep 03; Vol. 19 (9), pp. e0305848. Date of Electronic Publication: 2024 Sep 03 (Print Publication: 2024).
DOI: 10.1371/journal.pone.0305848
Abstrakt: Intracellular delivery of large molecule cargo via cell penetrating peptides (CPPs) is an inefficient process and despite intense efforts in past decades, improvements in efficiency have been marginal. Utilizing a standardized and comparative analysis of the delivery efficiency of previously described cationic, anionic, and amphiphilic CPPs, we demonstrate that the delivery ceiling is accompanied by irreparable plasma membrane damage that is part of the uptake mechanism. As a consequence, intracellular delivery correlates with cell toxicity and is more efficient for smaller peptides than for large molecule cargo. The delivery of pharmaceutically relevant cargo quantities with acceptable toxicity thus seems hard to achieve with the CPPs tested in our study. Our results suggest that any engineered intracellular delivery system based on conventional cationic or amphiphilic CPPs, or the design principles underlying them, needs to accept low delivery yields due to toxicity limiting efficient cytoplasmic uptake. Novel peptide designs based on detailed study of uptake mechanisms are required to overcome these limitations.
Competing Interests: All authors are current employees of Genentech, Inc., a member of the Roche Group, and may hold stock and options. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2024 Polderdijk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
Databáze: MEDLINE
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