A Mesoporous Silica-Based Naringenin Delivery System Promoting Macrophage M2 Polarization in Atherosclerosis

Atherosclerosis is the leading cause of global cardiovascular morbidity and mortality associated with inflammatory and immunological mechanisms. Immunotherapy has demonstrated promising efficacy in the management of atherosclerosis. Nevertheless, certain immunotherapeutic approaches are associated with limitations, including suboptimal efficacy and non-negligible adverse effects. Upon the pivotal role of macrophage phenotypes in atherosclerosis progression, naringenin-loaded manganese-doped mesoporous silica nanoparticles (MMSN@NAR) were designed and synthesized to reprogram M1 macrophages toward the M2 phenotype, thereby offering a potential therapeutic strategy for atherosclerosis treatment. High loading capacity of naringenin was achieved in MMSN carriers, with superior biocompatibility profiles compared to naringenin dissolved in dimethyl sulfoxide, while maintaining pH-dependent release behavior as demonstrated by dialysis assays. MMSN@NAR is preferentially phagocytosed by M1 macrophages, attenuates inflammatory responses, protects against oxidative stress, and promotes M2 polarization via the AMP-activated protein kinase (AMPK) pathway in vitro. In the ApoE^-/- mouse unilateral carotid artery ligation model of atherosclerosis, MMSN@NAR demonstrated marked accumulation in plaques and excellent biocompatibility. Compared to using naringenin or MMSN alone, it could further reduce plaque area by approximately 40% or 60% by inducing macrophage phenotype transformation, which was confirmed by section staining and immunofluorescence. Collectively, this study highlights enhanced macrophage M2 polarization inhibiting atherosclerosis by MMSN@NAR as a promising nanoplatform, offering a novel therapeutic approach based on anti-inflammatory immune regulation.