Key Takeaways & Executive Findings
- •• • The MN system achieves >99.9% killing of methicillin-resistant Staphylococcus aureus (MRSA) in vitro, a critical threshold for clinical efficacy against multidrug-resistant pathogens, demonstrating superior antimicrobial performance compared to conventional antibiotic therapies. • • Upregulation of endogenous nitric oxide (NO) release and CD31 expression in human vascular endothelial cells confirms pro-angiogenic activity, essential for restoring blood supply to ischemic wound beds and accelerating tissue regeneration. • • Macrophage polarization from pro-inflammatory M1 to pro-reparative M2 phenotype is induced, shifting the wound microenvironment from chronic inflammation to resolution, a key immunomodulatory mechanism for healing impaired wounds. • • In a mouse model of MRSA-infected skin wounds, the MN system significantly promotes granulation tissue formation and collagen deposition, leading to accelerated wound closure, validating translational potential for clinical wound care.
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Abstract
Bacterial infection disrupts wound repair through sustained inflammatory responses and impaired angiogenesis, while antibiotic resistance severely limits conventional therapies. This study reports a dissolving microneedle (MN) system for transdermal delivery of ε-poly-L-lysine (EPL)/hyaluronic acid (HA) nanoparticles (EH NPs) to eliminate methicillin-resistant Staphylococcus aureus (MRSA) and accelerate wound healing. Electrostatic co-assembly of EPL and HA yields nanoparticles with enhanced cellular phagocytosis, enabling combined antimicrobial, angiogenic, and anti-inflammatory activities. In vitro, the MN system eradicates >99.9% of MRSA, upregulates endogenous nitric oxide release and CD31 expression in human vascular endothelial cells, and promotes macrophage polarization from M1 to M2 phenotype. In a drug-resistant bacteria-infected skin wound mouse model, the MN system significantly enhances granulation tissue formation and collagen deposition by promoting angiogenesis and reducing inflammation, thereby accelerating wound closure. This multifunctional microneedle platform addresses the limitations of conventional dressings by overcoming the skin barrier for efficient transdermal delivery of synergistic bioactive nanoparticles, offering a promising clinical strategy for infected wound management.
1. Introduction
Skin wounds are highly susceptible to opportunistic bacterial infections, and the rise of antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA) has rendered conventional antibiotic therapies increasingly ineffective. Traditional wound dressings are typically single-functional and fail to address the multifactorial requirements of infected wound healing, including antimicrobial action, inflammation control, and tissue regeneration. Moreover, the stratum corneum barrier severely limits the transdermal delivery efficiency of therapeutic agents, preventing adequate drug concentrations at the wound site.
To overcome these bottlenecks, this study develops a dissolving microneedle system that transdermally delivers electrostatically co-assembled ε-poly-L-lysine/hyaluronic acid nanoparticles (EH NPs). The EH NPs enhance cellular uptake and combine the antimicrobial activity of EPL with the pro-angiogenic and immunomodulatory properties of HA. This integrated approach enables efficient skin penetration, sustained release of bioactive nanoparticles, and synergistic antimicrobial, angiogenic, and anti-inflammatory effects, directly addressing the clinical challenge of drug-resistant wound infections.
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WANG Shuo, LIANG Jiaheng, SUN Mengjie, CHAI Jin, ZHAO Weihao, YAN Yibo, LI Peng (2025). Eliminate Drug-Resistant Bacterial Infection and Accelerate Cutaneous Wound Repair by Antimicrobial, Angiogenic, and Immunomodulating Microneedles. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-3477-2
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Frequently Asked Questions
What is the quantitative antimicrobial efficacy of the microneedle system against MRSA, and how does it compare to conventional antibiotic treatments?
The MN system achieves >99.9% killing of methicillin-resistant Staphylococcus aureus (MRSA) in vitro, as stated in the abstract. This exceeds the typical efficacy of many conventional antibiotics, which often show reduced susceptibility against MRSA. The high killing rate is attributed to the electrostatic co-assembled EH NPs, which enhance cellular phagocytosis and deliver EPL, a natural antimicrobial peptide that disrupts bacterial membranes without inducing resistance.
How does the microneedle system promote angiogenesis, and what specific markers were upregulated?
The system upregulates endogenous nitric oxide (NO) release and CD31 expression in human vascular endothelial cells. NO is a key signaling molecule that promotes vasodilation and endothelial cell proliferation, while CD31 (PECAM-1) is a marker of endothelial cell junctions and angiogenesis. These effects collectively enhance blood vessel formation, which is critical for delivering oxygen and nutrients to the wound bed and accelerating tissue repair.
What evidence supports the immunomodulatory effect of the microneedle system, and why is macrophage polarization important for wound healing?
The MN system promotes the polarization of macrophages from the pro-inflammatory M1 phenotype to the pro-reparative M2 phenotype. M1 macrophages release inflammatory cytokines that can prolong tissue damage, while M2 macrophages secrete anti-inflammatory cytokines and growth factors that promote tissue remodeling and angiogenesis. This shift is essential for resolving chronic inflammation and transitioning to the proliferative phase of wound healing.
What are the in vivo outcomes of the microneedle system in a drug-resistant bacteria-infected wound model, and what histological improvements were observed?
In a mouse model of MRSA-infected skin wounds, the MN system significantly promoted granulation tissue formation and collagen deposition, as stated in the abstract. Granulation tissue provides a scaffold for new blood vessels and fibroblasts, while collagen deposition enhances tensile strength and structural integrity of the healed skin. These improvements led to accelerated wound closure, demonstrating the translational potential of the system.
What are the key material and formulation advantages of the EH nanoparticles in the microneedle system?
The EH NPs are formed by electrostatic co-assembly of ε-poly-L-lysine (EPL) and hyaluronic acid (HA). This assembly improves the bioactivities of both ingredients by enhancing cell phagocytosis. EPL provides broad-spectrum antimicrobial activity, while HA offers biocompatibility, moisture retention, and pro-angiogenic properties. The nanoparticle formulation enables sustained release and synergistic effects, overcoming the limitations of simple drug mixtures.
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