Macrophage membrane-camouflaged dual drug-based biomimetic pH-responsive nanomedicine for synergistic antifungal-antioxidant therapy in oral candidiasis

The escalating challenges of antifungal drug resistance, toxicity, and limited therapeutic strategies for oral candidiasis (OC) necessitate innovative treatment approaches. This study developed a pH-responsive baicalein-based nanocarrier by coupling baicalein with phenylboronic acid-functionalized polymethyl vinyl ether-maleic anhydride to encapsulate amphotericin B (AMB). The nanocarrier was further camouflaged with macrophage membranes, forming a biomimetic dual-drug nanoplatform (MPPB@A NPs) for synergistic antifungal-antioxidant therapy against OC. MPPB@A NPs leverage macrophage membrane coating to enhance active targeting of β-glucans on C. albicans , while borate ester bonds enable pH-responsive drug release at pH 5.5. MPPB@A NPs were demonstrated to effectively disrupt C. albicans biofilms and scavenge reactive oxygen species (ROS). In murine OC models, MPPB@A NPs significantly reduced oral fungal burden (11.17% of the free AMB group) and alleviated oxidative stress. Subsequently, ROS-mediated inflammation was reduced. Furthermore, MPPB@A NPs exhibited the favorable biocompatibility, including hemolysis rates below 5%, reduced cytotoxicity, and significantly lower nephrotoxicity compared to free AMB. Therefore, this study provides a promising strategy to overcome AMB toxicity and resistance while promoting the synergistic antifungal-antioxidant therapy for OC management. Statement of Significance Current oral candidiasis therapies face challenges of drug resistance and systemic toxicity. This study has the potential to address these limitations using a biomimetic nanoplatform combining macrophage membrane camouflage with a pH-responsive carrier, enabling targeted dual-drug delivery to infection sites. The membrane coating facilitates tissue accumulation, while pH-triggered release delivers amphotericin B within acidic fungal biofilms, disrupting Candida albicans. Baicalein, as a nanocarrier component, exhibits antioxidant and anti-inflammatory effects. This strategy synergistically combats fungal infection and associated oxidative stress damage while significantly enhancing drug biocompatibility and reducing systemic toxicity, offering a clinically translatable solution.