Abstract
Chronic inflammation is a major cause for the pathogenesis of musculoskeletal diseases such as fragility fracture, and nonunion. Studies have shown that modulating the immune phenotype of macrophages from proinflammatory to prohealing mode can heal recalcitrant bone defects. Current therapeutic strategies predominantly apply biochemical cues, which often lack target specificity and controlling their release kinetics in vivo is challenging spatially and temporally. We show a magnetic iron-oxide nanocomplexes (MNC)-based strategy to resolve chronic inflammation in the context of promoting fracture healing. MNC internalized pro-inflammatory macrophages, when coupled with an external magnetic field, exert an intracellular magnetic force on the cytoskeleton, which promotes a prohealing phenotype switch. Mechanistically, the intracellular magnetic force perturbs actin polymerization, thereby significantly reducing nuclear to cytoplasm redistribution of MRTF-A and HDAC3, major drivers of inflammatory and osteogenic gene expressions. This significantly reduces Nos2 gene expression and subsequently downregulates the inflammatory response, as confirmed by quantitative PCR analysis. These findings are a proof of concept to develop MNC-based resolution-centric therapeutic intervention to direct macrophage phenotype and function towards healing and can be translated either to supplement or replace the currently used anti-inflammatory therapies for fracture healing.