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<p>This study aims to develop a multifunctional polymer nanovesicle system, AG86-β-glucan-poly(methionine-b-carboxybetaine) (AGPMC), which integrates AG86 peptide (a targeting ligand for the α6β4 integrin on basal keratinocytes) and reactive oxygen species (ROS) responsiveness to enhance the transdermal delivery of ergothioneine (EGT). The objective is to overcome the limitations of hydrophilic drug delivery and provide a targeted, ROS-triggered strategy for treating skin lipofuscin. AGPMC was synthesized via RAFT and ROP polymerization and self-assembles into stable nanovesicles (ANVs). Physicochemical characterization confirmed that the unloaded ANVs have an average size of 106.17 ± 3.26 nm and a polydispersity index (PDI) of 0.261 ± 0.027, with excellent stability and clear ROS-triggered structural responsiveness. After EGT loading, the nanovesicles exhibited a size of 140.10 ± 3.33 nm and a PDI of 0.217 ± 0.008. <i>In vitro</i> studies using HaCaT cells demonstrated a significant enhancement in cellular uptake, with an increase of up to 2.2-fold compared to free FSS (<i>p</i> &lt; 0.0001), as well as effective ROS scavenging and minimal cytotoxicity. The endocytosis mechanism study revealed that ANVs are primarily taken up via energy-dependent active transport, with caveolae-mediated endocytosis being the main pathway. Moreover, transdermal delivery studies confirmed that EGT-loaded nanovesicles significantly improved drug penetration through the stratum corneum. This work represents the first application of the AG86-conjugated nanovesicles for keratinocyte-targeted delivery, combined with ROS responsiveness. The “Loading-Targeting-Responding “ strategy holds significant potential for enhancing hydrophilic drug delivery and offers a promising approach for treating age-related skin lipofuscin accumulation.</p> Graphical Abstract <p>Targeted delivery of EGT via the “Loading-Targeting-Responding” strategy.</p> <p></p>

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AG86 Peptide-modified Reactive Oxygen Species-responsive Polymer Nanovesicles for Transdermal Delivery of Hydrophilic Ergothioneine to Basal Keratinocytes

  • 期刊论文

  • 发表日期：

    2025年5月9日

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  • Junlong Chen,
  • Yiqing Long,
  • Xiaozeliang Zhou,
  • Zongning Yin

摘要

This study aims to develop a multifunctional polymer nanovesicle system, AG86-β-glucan-poly(methionine-b-carboxybetaine) (AGPMC), which integrates AG86 peptide (a targeting ligand for the α6β4 integrin on basal keratinocytes) and reactive oxygen species (ROS) responsiveness to enhance the transdermal delivery of ergothioneine (EGT). The objective is to overcome the limitations of hydrophilic drug delivery and provide a targeted, ROS-triggered strategy for treating skin lipofuscin. AGPMC was synthesized via RAFT and ROP polymerization and self-assembles into stable nanovesicles (ANVs). Physicochemical characterization confirmed that the unloaded ANVs have an average size of 106.17 ± 3.26 nm and a polydispersity index (PDI) of 0.261 ± 0.027, with excellent stability and clear ROS-triggered structural responsiveness. After EGT loading, the nanovesicles exhibited a size of 140.10 ± 3.33 nm and a PDI of 0.217 ± 0.008. In vitro studies using HaCaT cells demonstrated a significant enhancement in cellular uptake, with an increase of up to 2.2-fold compared to free FSS (p < 0.0001), as well as effective ROS scavenging and minimal cytotoxicity. The endocytosis mechanism study revealed that ANVs are primarily taken up via energy-dependent active transport, with caveolae-mediated endocytosis being the main pathway. Moreover, transdermal delivery studies confirmed that EGT-loaded nanovesicles significantly improved drug penetration through the stratum corneum. This work represents the first application of the AG86-conjugated nanovesicles for keratinocyte-targeted delivery, combined with ROS responsiveness. The “Loading-Targeting-Responding “ strategy holds significant potential for enhancing hydrophilic drug delivery and offers a promising approach for treating age-related skin lipofuscin accumulation.

Graphical Abstract

Targeted delivery of EGT via the “Loading-Targeting-Responding” strategy.