Effective resistance to UVB-induced skin damage through the encapsulation of chebulinic acid in mulberry-derived exosome-like nanoparticles

Abstract

Ultraviolet-B (UVB) radiation induces significant skin damage by penetrating into the dermal layer, leading to reactive oxygen species (ROS) generation and triggering cellular necrosis and apoptosis. Conventional sunscreens focus primarily on UVB blocking but are limited in their ability to repair dermal damage due to insufficient permeability. In this study, we discover that chebulinic acid (CA), one of the principal monomers in Terminalia chebula Retz., has superior efficacy in promoting recovery from UVB-induced skin damage compared with other major monomers. Mechanistically, CA’s anti-UVB function involves regulating the expression of IL-6 and IFN-β through activation of the MAPK pathway. To overcome the formidable barrier posed by the skin, we identify mulberry exosome-like nanoparticles (MELNs) as an efficient transdermal delivery system and develop CA@MELNs loaded with CA. Furthermore, we demonstrate that the dissociative CA within the CA@MELNs delivery system significantly enhances both transdermal penetration and anti-UVB efficiency in vitro and in vivo. Our findings suggest the substantial potential of CA as an effective ingredient and CA@MELNs as a robust and accessible platform for mitigating UVB damage.

1. Introduction

As the concentration of greenhouse gases continues to rise, the depletion of the Earth’s ozone layer has led to a gradual increase in the amount of solar ultraviolet (UV) radiation reaching the Earth’s surface. UV radiation, particularly within the UVB spectrum (280–320 nm), poses significant threats to cutaneous health through various mechanisms. Although UVB accounts for only 1%–10% of total terrestrial UV exposure, its high-energy photons cause direct DNA damage, resulting in carcinogenic effects on the skin through the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts. Simultaneously, UVB radiation generates reactive oxygen species (ROS), which induce oxidative stress, inflammation, and apoptosis [1–3]. Chronic UVB exposure disrupts epidermal homeostasis, accelerating photoaging through collagen degradation and promoting carcinogenesis [4,5]. Although conventional sunscreens utilize synthetic filters such as oxybenzone and avobenzone, increasing concerns regarding their endocrine-disrupting potential, photostability limitations, and inability to mitigate secondary oxidative damage necessitate the exploration of natural phytochemical alternatives with intrinsic antioxidant and UV-absorbing properties.

Numerous natural Chinese medicine products have been shown to have anti-UVB effects. Fruits of Terminalia chebula Retz. (T. chebula Retz.), revered as the “King of Tibetan Medicine”, has emerged as a compelling candidate for photoprotective phytochemical discovery. Phytochemical analyses revealed that T. chebula synthesizes hydrolyzable tannins such as chebulinic acid (CA), which is a polyphenolic compound that scavenges ROS and has anti-inflammatory and antiapoptotic activities [6–8]. ROS is highly correlated with skin damage caused by ultraviolet radiation [9–11], but the relationship between CA and UVB has not been reported to date. The therapeutic potential of CA is constrained by the formidable barrier of the skin [12]: its molecular weight (~956 Da) exceeds the 500 Da threshold for passive transdermal diffusion, whereas its polar groups impede lipid bilayer penetration.

To address the bioavailability challenge, transdermal delivery nanocarriers have been employed. Specifically, plant-derived exosome-like nanoparticles (PELNs), which are naturally evolved nanocarriers for intercellular biomolecule transport, have shown promise. PELNs possess several advantages: (1) their lipid bilayer structure (50–150 nm in diameter) facilitates fusion with epidermal membranes, thereby bypassing the size exclusion limit of the stratum corneum; (2) high deformability allows for intercellular penetration without compromising the integrity of the skin barrier; and (3) the presence of endogenous phospholipids enhances cargo solubility and biocompatibility while minimizing immunogenicity. Importantly, the lipophilic nature of PELNs facilitates the dermal delivery of hydrophobic phytochemicals, while their plant origin ensures superior biodegradability and cutaneous tolerability compared with synthetic nanocarriers [13–15].

This study pioneers the integration of the phytochemical legacy of Tibetan medicine with cutting-edge nanobiotechnology, establishing CA@MELNs as a biocompatible platform for advanced topical photoprotection. By elucidating the mechanistic interplay between CA-induced ROS scavenging and MELN delivery efficacy, we expand the translational potential of PELNs.