Macrophages-mediated atherosclerosis (AS) is an inflammatory disease and the most common cause of ischemia. With the progress of basic and clinical research, anti-cytokine therapy has garnered considerable attention of the research community for the regulation of the inflammatory microenvironment for AS treatment. Despite of their promising potential, primary clinical trials have revealed that anti-cytokine drugs exhibit poor selectivity and thus affect other parts of the immune system, especially during long-term management. To circumvent these limitations, herein we exploited mesoporous silica nanoparticles (MSNs) with a pore size of 15.5 nm as carriers for the anti-interleukin-1β (anti-IL-1β) delivery to be the anti-cytokine agents. In vitro mechanistic studies indicated that the MSNs@anti-IL-1β can regulate the macrophage-related inflammatory microenvironment, promote the viability of vascular endothelial cells (vECs), and reduce proliferation and phenotypic switching of vascular smooth muscle cells (vSMCs). In vivo evaluation further revealed that the MSNs@anti-IL-1β were preferentially accumulated in macrophages, impeding the AS progress by maintaining the endothelium integrity and inhibiting the vSMCs proliferation. Besides, MSNs@anti-IL-1β induced neovascularization and improved hindlimb ischemia regeneration. Taken together, these MSNs affording the sustained release of anti-cytokine agents may have broad implications for the clinical management of the AS, including the reduction of the AS progression and alleviation of the ischemia.