Chirality-Dependent Reprogramming of Macrophages

The chirality of materials directly influences their transport and biological effects in physiological conditions. However, the impact of chiral materials on cellular metabolic reprogramming remains incompletely elucidated. In this study, we have synthesized chiral gold particles through a light-driven particle growth approach and demonstrated that d-Au particles exhibited superior macrophage activation ability compared to l-Au particles. An inflammatory creatine–phosphocreatine shunt was induced following d-Au stimulation. This shunt, facilitated by the upregulated expression of creatine kinase muscle-type (CKM), also resulted in a reduction in cytosolic levels of creatine. Pharmacological inhibition and genetic ablation of CKM further suppressed the secretion of pro-inflammatory cytokines, without compromising mitochondrial respiration. Moreover, the activation of macrophages induced by d-Au was mediated through the activation of the NF-κB and NLRP3 inflammasome pathways. Inhibition of CKM expression not only decreased the secretion of CXCL2 but also attenuated IL-1β by suppressing the NLRP3 inflammasome pathways. Our investigation into the metabolic reprogramming mechanism of chiral materials on macrophage activation is pivotal for the application of chiral-based anticancer therapies.