Adaptive Nanoparticle-Mediated Modulation of Mitochondrial Homeostasis and Inflammation to Enhance Infected Bone Defect Healing

Abstract

Infected bone defects (IBDs) exhibit impaired healing due to excessive inflammation triggered by pathogen-associated molecular patterns (PAMPs) from bacteria. As a vital factor in orchestrating immune responses, mitochondrial homeostasis maintenance is central to inflammation blockade. This research developed a chameleon-like nanoplatform by covering hydroxyapatite nanoparticles with a cerium ion coordinated tannic acid supramolecular network (HA@Ce-TA), which adaptively functions to regulate mitochondrial homeostasis based on intra- and extracellular environments. Extracellularly, acidic conditions activate HA@Ce-TA's peroxidase/oxidase-mimicking activity to produce reactive oxygen species (ROS), and external near-infrared (NIR) irradiation excites nanoscale Ce-TA to produce hyperthermia, which is found and explained by chemical computation. ROS production with photothermal therapy can eliminate bacteria effectively and reduce mitochondrial stress. Intracellularly, HA@Ce-TA remodels mitochondrial dynamics by upregulating mitochondrial fusion genes and eliminates excessive ROS by mimicking superoxidase/catalase. Consequently, this comprehensive modulation of mitochondrial homeostasis inhibits inflammasome overactivation. <i>In vitro</i> and <i>in vivo</i> studies showed HA@Ce-TA can modulate the mitochondria-centered inflammatory cascade to enhance IBD treatment, highlighting the potential of engineering nanotherapeutics to recalibrate mitochondrial homeostasis as an infected disease-modifying intervention.