Potassium-Doped MnO2 Nanoparticles Reprogram Neutrophil Calcium Signaling to Accelerate Healing of Methicillin-Resistant Staphylococcus aureus-Infected Diabetic Wounds

Abstract

Neutrophils, as first-line immune cells, typically lose their edge within the diabetic wounds accompanied by methicillin-resistant Staphylococcus aureus (MRSA) infections (the D/M setting), playing the role of “more foe than friend” during the healing process. Specifically, reduced influx of calcium ions (Ca²⁺) and impaired calcium homeostasis yield the dysfunction of neutrophil sequential behaviors in pathogen killing and wound healing, manifesting as suppressed chemotaxis, decreased intracellular reactive oxygen species (ROS) generation, prolonged apoptosis, and retention of neutrophil extracellular traps (NETs). To address this challenge, this study fabricated potassium (K)-doped manganese dioxide nanoparticles (MnO₂ NPs), which activated transmembrane Ca²⁺ channels by inducing neutrophil depolarization via electron transfer. Subsequently, this contributed to the initial Ca²⁺ influx and reprogrammed Ca²⁺-dependent behaviors of impaired neutrophils. Also, the potential antimicrobial capacity of K-MnO₂ NPs created a favorable extracellular environment that restored calcium homeostasis, enabling apoptotic neutrophils to be removed timely. Therefore, the wounds treated with K-MnO₂ NPs in the D/M setting exhibited potent resistance to MRSA and rapid healing, which could be attributed to the synergistic effects of K-MnO₂ NPs in leveraging Ca²⁺ influx and maintaining calcium homeostasis. In brief, K-MnO₂ NPs constitute an effective strategy to resist MRSA and rapid wound healing in the D/M setting.