Mechanical force initiates sterile inflammation, a process implicated in diverse physiological and pathological processes. The timely clearance of apoptotic cells by macrophages via efferocytosis is crucial for the proper resolution of sterile inflammation and for averting excessive tissue damage. Despite this, the specific role and underlying mechanisms of mechanical force on macrophage efferocytosis remain obscure. By integrating bioinformatics and metabolomics analyses, we uncovered how mechanical force disrupts the "arginine metabolism─TCA cycle─mitochondrial function" metabolic cascade, thereby impairing macrophage efferocytosis and intensifying sterile inflammation. Notably, we discovered that elevating l-arginine levels can ameliorate these crises by restoring energy metabolism. Leveraging this insight, we engineered a microneedle drug delivery system loaded with nitric-oxide driven nanomotors (MSN-LA@MNs) for targeted delivery of l-arginine. The active component, MSN-LA, exploits the heightened expression of inducible nitric oxide synthase (iNOS) in force-loaded tissues as a chemoattractant, harnessing NO generated from iNOS-catalyzed l-arginine for autonomous propulsion. In a force-induced rat orthodontic tooth movement (OTM) model, we confirmed that MSN-LA@MNs enhance macrophage efferocytosis and, under iNOS guidance, dynamically modulate sterile inflammation levels in OTM, thus facilitating the OTM process. Collectively, our findings elucidate previously unclear mechanistic links between force, macrophage efferocytosis, and sterile inflammation from a metabolic vantage point, offering a promising targeted strategy for modulating force-related biological processes such as OTM.
Keywords: efferocytosis; energy metabolism; l-arginine; mechanical force; microneedle; nanomotor.