The co-assembled hesperidin-emodin nanospindles for synergistic enhancement of regenerative repair in MRSA-infected incisions

Pathogen colonization, uncontrolled inflammation, and impaired tissue repair impede infected wound healing. Among natural products, hesperidin (HSD) and emodin (EMO) showed wound-healing and antibacterial potential, respectively. However, their poor solubility and low bioavailability significantly restrict the therapeutic efficacy in infected wounds. Thus, we developed co-assembled nanoparticles (HE NPs), in which HSD and EMO self-assembled into a core-shell spindle structure. Specifically, HSD localized at the core, while EMO formed J-type aggregates surrounding it, which were stabilized by hydrogen bonds and π-π stacking at the interface. This configuration ingeniously integrated the functions of HSD and EMO, enhancing solubility, enabling sequential drug release, and providing full-cycle treatment for methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. In vitro, HE NPs eradicated MRSA by physically disrupting cell membranes and chemically inhibiting bacterial metabolism, while reducing inflammation and promoting angiogenesis. In vivo, HE NPs suppressed inflammation and accelerated tissue regeneration by modulating the NF-κB and JAK-STAT pathways, leading to nearly complete wound closure (≈100%) in MRSA-infected mice. Notably, HE NPs, which are based on natural products, are highly biocompatible and drug-resistance-free, providing an alternative for infected wound healing.