Report on the Academic Paper

Inflammatory skin diseases, such as psoriasis and rosacea, are common chronic skin conditions worldwide, significantly impacting patients’ quality of life. Traditional topical drug delivery methods, while simple and non-invasive, suffer from poor skin penetration and long-term side effects. Therefore, developing an effective and safe topical treatment regimen has become a key focus of current research.

Oxidative stress plays a crucial role in the pathogenesis of many inflammatory skin diseases, including psoriasis and rosacea. Excessive accumulation of reactive oxygen species (ROS) reduces the skin’s physiological antioxidant capacity and disrupts the redox system of the epidermal microenvironment. Studies have shown that superoxide dismutase (SOD) and matrix metalloproteinase 9 (MMP9) play important roles in the onset and progression of inflammatory skin diseases. Thus, targeting the enzymatic activities of SOD and MMP9 may be an effective strategy for treating these conditions.

Nanoparticles (NPs), due to their controllable size, shape, and unique physicochemical properties, have shown advantages in immunomodulation, vaccination, and the treatment of inflammatory diseases. Notably, gold nanoparticles (AuNPs) possess SOD enzymatic activity, effectively scavenging excess ROS and modulating inflammation. However, their transdermal properties and stability limit their application in inflammatory skin diseases. Surface modification can improve the transdermal properties and stability of metal nanoparticles. This study developed a novel biological nanomaterial, Au-MEA NPs, by combining azelamide monoethanolamine (MEA) with gold nanoparticles, aiming to enhance their stability and transdermal properties for effective treatment of inflammatory skin diseases.

Source of the Paper

The paper was co-authored by He Zhao, Han Zhao, Yan Tang, Mengfan Li, Yisheng Cai, Xin Xiao, Fanping He, Hongwen Huang, Yiya Zhang, and Ji Li, affiliated with the Department of Dermatology at Xiangya Hospital of Central South University, the College of Materials Science and Engineering at Hunan University, and other institutions. The paper was published in 2024 in the journal Biomarker Research.

Research Process and Experimental Design

1. Material Synthesis

1.1 Synthesis of Au-CA NPs

Au-CA NPs were synthesized using the classic sodium citrate reduction method. The process involved heating a chloroauric acid (HAuCl₄) solution to 105°C, adding sodium citrate solution, and reacting to form Au-CA NPs. After the reaction, the NPs were separated by centrifugation and dispersed in deionized water.

1.2 Synthesis of Au-MEA NPs

Au-MEA NPs were synthesized via a ligand exchange method. Au-CA NPs were mixed with an MEA solution and stirred at 30°C for 24 hours, allowing the MEA ligands to replace the citrate ligands. The reaction was followed by centrifugation and dispersion in deionized water.

1.3 Synthesis of FITC-Labeled Au-CA NPs and Au-MEA NPs

FITC-labeled NPs were prepared by reacting Au-CA NPs and Au-MEA NPs with 3-mercaptopropionic acid (MPA) and then conjugating with fluorescein isothiocyanate (FITC).

1.4 Preparation of Au-CA NPs Gel and Au-MEA NPs Gel

Au-CA NPs and Au-MEA NPs were mixed with Sepimax Zen gel, dispersed via ultrasonication, and stirred to form homogeneous gels.

2. Material Characterization

The physicochemical properties of Au-CA NPs and Au-MEA NPs were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and dynamic light scattering (DLS).

3. Cell Experiments

An inflammatory cell model was established using HaCaT cells (human keratinocytes). The cytotoxicity of the NPs was assessed via CCK-8 assay, intracellular distribution was observed using fluorescence microscopy and TEM, and the expression of inflammatory factors was detected via quantitative real-time PCR (qPCR) and Western blot.

4. Animal Experiments

The therapeutic effects of Au-MEA NPs gel were evaluated using imiquimod (IMQ)-induced psoriasis and LL37-induced rosacea models. Transdermal performance and safety were assessed via histological analysis, immunofluorescence, and ICP-MS.

5. Proteomic Analysis

The therapeutic mechanisms of Au-MEA NPs in inflammatory skin diseases were analyzed using proteomics, identifying differentially expressed proteins (DEPs) and performing GO and KEGG pathway enrichment analyses.

Main Research Findings

1. Synthesis and Characterization of Au-MEA NPs

Au-MEA NPs were successfully synthesized via ligand exchange, exhibiting good stability and transdermal properties. TEM and XRD analyses showed that Au-MEA NPs had similar morphology and size distribution to Au-CA NPs. UV-Vis and FTIR spectra confirmed the successful attachment of MEA ligands. DLS analysis indicated that Au-MEA NPs had a larger average size in aqueous solution and a lower Zeta potential, suggesting greater stability.

2. Transdermal Performance of Au-MEA NPs Gel

SEM and EDS analyses confirmed the successful embedding of Au-CA NPs and Au-MEA NPs in the gel. TEM and ICP-MS analyses demonstrated that Au-MEA NPs effectively penetrated the stratum corneum of mouse skin and accumulated in the dermis.

3. Therapeutic Effects of Au-MEA NPs Gel on Psoriasis and Rosacea

In the IMQ-induced psoriasis model, Au-MEA NPs gel significantly reduced ear thickness, scaling, and erythema in mice, and decreased epidermal hyperplasia and dermal infiltrating cells. In the LL37-induced rosacea model, Au-MEA NPs gel markedly improved erythema and inflammatory cell infiltration and suppressed the expression of inflammatory factors.

4. Anti-Inflammatory Mechanisms of Au-MEA NPs

Proteomic analysis revealed that Au-MEA NPs modulated inflammation-related pathways, including NF-κB signaling, TNF signaling, and Th17 cell differentiation. Additionally, Au-MEA NPs reduced the production of inflammatory mediators in keratinocytes by promoting SOD activity and inhibiting MMP9 activity.

5. Safety of Au-MEA NPs

Histological analysis and ICP-MS detection showed that Au-MEA NPs gel did not cause significant toxicity in major organs of mice, indicating good safety.

Conclusions and Significance

This study successfully synthesized Au-MEA NPs via ligand exchange and demonstrated their significant therapeutic effects in treating inflammatory skin diseases such as psoriasis and rosacea. Au-MEA NPs alleviated skin inflammation by promoting SOD activity and inhibiting MMP9 activity, thereby reducing the production of inflammatory mediators. Furthermore, Au-MEA NPs exhibited excellent transdermal properties and safety, showing great potential for clinical translation.

Research Highlights

1. Synthesis of Novel Nanomaterials: Au-MEA NPs were successfully synthesized via ligand exchange, significantly improving the stability and transdermal properties of gold nanoparticles.
2. Significant Anti-Inflammatory Effects: Au-MEA NPs showed superior therapeutic effects in psoriasis and rosacea animal models compared to traditional Au-CA NPs.
3. In-Depth Mechanistic Studies: Proteomic analysis revealed that Au-MEA NPs exert anti-inflammatory effects by modulating the NF-κB signaling pathway and SOD/MMP9 activity.
4. Good Safety Profile: Au-MEA NPs did not cause significant toxicity in major organs of mice, demonstrating good safety.

Future Prospects

Although Au-MEA NPs show great potential in treating inflammatory skin diseases, their long-term toxicity, transdermal mechanisms, and penetration depth require further investigation. Future work will include optimizing therapeutic doses and frequencies, as well as comparative studies with existing commercial gels to further enhance their performance.