Fluorous oligoarginines as supra-enhancers for intracellular and transdermal peptide delivery

Peptides are increasingly recognized as important therapeutics due to their specificity and potency. However, their clinical application is often hindered by numerous barriers, including low bioavailability, poor cell membrane and tissue penetration. To address these limitations, we developed a library of fluorous penetrating peptides and identified fluorinated hexa-arginine (FR6) as a super-enhancer for cell and tissue penetration. FR6 markedly enhances the intracellular delivery of a variety of peptides by improving membrane permeability, facilitating their uptake across diverse cell types. It greatly improves the penetration of bioactive peptides in 3D tumor spheroids, allowing for improved therapeutic efficacy. More importantly, FR6 demonstrates remarkable potential for transdermal delivery of peptide drugs, effectively enhancing the penetration of peptides like acetyl hexapeptide-8 for treating UVB-induced skin photoaging. Our findings underscore the use of FR6 as a super-enhancer in overcoming multiple physiological barriers during cell, tissue and transdermal delivery. • Fluorous hexa-arginine (FR6) was identified from a fluorous cationic peptides library for superior cellular uptake. • The fluorous tag is critical for FR6’s highly efficient cellular internalization and endosomal escape. • FR6 enables deep penetration in 3D tumor spheroids and enhances in vivo antitumor efficacy of a pro-apoptotic peptide. • FR6 facilitates transdermal delivery of cargo peptides to depths of approximately 600 μm in mouse skin. • The FR6/AHP-8 effectively treats UVB-induced skin photoaging with good biocompatibility.