Multilamellar Ceramide‐Based Nanocarriers: Enhanced Skin Barrier Repair Through Synergistic Supplementation and Bioavailability Modulation

ABSTRACT

Ceramide deficiency in the stratum corneum (SC) is a key pathogenic factor in chronic inflammatory dermatoses such as atopic dermatitis. Conventional topical ceramide formulations face limitations, including poor stability, insufficient SC penetration, and a singular “passive supplementation” mechanism that lacks active modulation of skin barrier repair. A multilamellar ceramide nanocarrier (MLC) system was developed and characterized for enhanced cutaneous delivery and active modulation of keratinocyte barrier‐related gene expression. MLCs were prepared by thin‐film hydration and characterized by dynamic light scattering, cryogenic transmission electron microscopy, and high‐performance liquid chromatography (HPLC)‐charged aerosol detection. Skin permeation and deposition were evaluated using Franz diffusion cells with porcine skin. In vitro bioactivity was assessed in HaCaT keratinocytes by CCK‐8 and real‐time PCR (qPCR) of genes for ceramide synthesis (CERS3 and SPTLC2), epidermal differentiation (FLG, IVL, TGM1, and AQP3), and inflammation (TNF‐α, IL‐6, and IL‐8). MLCs represented 137.1 nm Z ‐average diameter (polydispersity index [PDI] 0.399), multilamellar morphology, and 98.2% ± 1.3% encapsulation efficiency. Ex vivo studies showed MLCs increased SC ceramide deposition (3.0‐fold) and viable epidermis/dermis delivery versus free ceramide, with <7% systemic permeation. In HaCaT cells, MLCs upregulated CERS3 (5.0‐fold), SPTLC2 (6.2‐fold), FLG (4.7‐fold), IVL (4.6‐fold), TGM1 (3.5‐fold), and AQP3 (5.6‐fold) at 0.1% and suppressed TNF‐α, IL‐6, and IL‐8 by 70%–85% ( p  < 0.001 vs. free ceramide). The MLC platform repairs skin barrier via efficient ceramide delivery and active gene upregulation with anti‐inflammatory effects, offering a promising therapy for ceramide‐deficient skin.

Practical Applications : The MLC platform offers a versatile and scalable formulation strategy for developing next‐generation skin barrier repair products. Unlike conventional ceramide formulations that merely supplement lipids, MLCs actively stimulate keratinocytes to upregulate endogenous ceramide synthesis and epidermal differentiation markers while suppressing inflammation. This dual mechanism enables formulators to achieve therapeutic efficacy at lower active ingredient concentrations, reducing production costs and minimizing potential skin irritation. The MLC technology is particularly suitable for topical products targeting atopic dermatitis, psoriasis, xerotic skin, and post‐procedure skin recovery. Its good stability at 4°C and high encapsulation efficiency (98.2%) support industrial‐scale manufacturing with consistent batch‐to‐batch quality, facilitating translation from laboratory research to commercial skincare and dermatological applications.