Metapanax delavayi (Franch.) J. Wen & Frodin (Araliaceae) is a plant with both medicinal and edible value, but there is no study examining its effects on skin neurogenic inflammation. We investigated the anti-neurogenic inflammatory and soothing potential of Metapanax delavayi extract (MDE) in vitro using SH-SY5Y cells activated by capsaicin and HaCaT cells stimulated by substance P, and in vivo using a heat-induced zebrafish model. We found that MDE significantly inhibited TRPV1 activation and intracellular calcium influx, down-regulated neuropeptides (CGRP, NGF, substance P) and proinflammatory cytokines (IL-1α, IL-6, IL-8), and regulated emotion-related hormones (decreased cortisol, increased β-endorphin). It also reduced heat-induced hypermotility in zebrafish. Critically, the mechanistic study suggests that biological activity may be associated with the inactivation of the CRHR1/POMC/MC1R signaling pathway. Collectively, these findings indicate that MDE possesses significant potential as a natural skincare ingredient for counteracting neurogenic inflammation associated with sensitive skin.
Li Zhou,Fangfang Duan,Yuting Zhang,Yicai Huang,Le Xu,Nan Zhang,Shiming Yang,Yi Ma,Bing Yang,Kai Lu
Hyperpigmentation is a skin disorder characterized by the abnormal accumulation of melanin, in which the melanocortin-1 receptor (MC1R) was recognized as a key target for melanin production. Antisense oligonucleotide (ASO), by targeting mRNA to inhibit protein synthesis, holds a promising gene therapy for hyperpigmentation. However, challenges such as nonspecific activation, off-target toxicity, and limited cellular permeability hinder their broader clinical application. Inspired by the Chinese proverb “Turn an enemy into a friend”, we introduce a dual-gated, ultraviolet (UV)-tyrosinase (TYR) cascade-responsive modified ASO (m-ASO) that enables spatiotemporally controlled silencing of MC1R. The engineered m-ASO is caged via thymidine modification, rendering it inactive until sequentially exposed to exogenous UV and intracellular TYR. UV irradiation, conventionally hyperpigmentation trigger, is repurposed to initiate decaging of m-ASO into an intermediate form, pH-ASO. This intermediate is then enzymatically activated by TYR overexpressed in melanocytes within pigmented tissues, ultimately restoring the native conformation and therapeutic function of the ASO. This “enemy-to-ally” strategy allows for disease-specific, precision activation of ASO therapeutics. Notably, to enhance transdermal delivery, the m-ASO nanocomplex is integrated into a biocompatible, dissolvable microneedle system for painless and localized epidermal administration. The resulting platform demonstrates precise MC1R silencing and effective melanin suppression, while sparing normal melanocytes. Together, this cascade-caged, cell-selective, and minimally invasive strategy presents a novel framework for programmable nucleic acid therapeutics in dermatological and enzyme-overexpressing diseases.
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