ROS-responsive nanoparticles embedded in oleogel promote scarless healing of MRSA-infected wounds through synergistic regulation of iron metabolism and collagen remodeling

Methicillin-resistant Staphylococcus aureus (MRSA) infection poses a major obstacle to skin wound healing, often accompanied by persistent inflammation and excessive scar formation. There is an urgent clinical need for more effective localized therapeutic strategies. In this study, we developed a responsive nano-oleogel system based on natural bioactive compounds for the synergistic treatment of MRSA-infected wounds. This system consists of self-assembled nanoparticles of hinokitiol and verteporfin (VP), embedded within an oleogel matrix constructed using β-sitosterol. The oleogel conforms well to irregular wound surfaces and enables stimuli-responsive drug release in the presence of reactive oxygen species (ROS) at the infection site. Hinokitiol chelates Fe³⁺ locally, disrupting bacterial iron metabolism and inducing membrane damage and DNA disruption, thereby achieving non-antibiotic bactericidal effects. β-Sitosterol contributes inherent anti-inflammatory activity, helping to modulate early immune responses. VP exerts its effects by inhibiting the Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ) signaling pathway. This multifunctional formulation demonstrates synergistic antibacterial, anti-inflammatory, and scar-modulating effects, offering a promising strategy for the treatment of infected chronic wounds. The animal experiments were approved by the Animal Experimental Research Center of Zhejiang Chinese Medical University and were conducted in accordance with the relevant guidelines and regulations (approval No. IACUC-20241125-07).