Spermine delivered by ZIF90 nanoparticles alleviates atherosclerosis by targeted inhibition of macrophage ferroptosis in plaque.

Abstract

Background: Nowadays, emerging evidence have suggested that the ferroptosis of macrophages could contribute to the progression of atherosclerosis (AS). Meanwhile, Spermine (Sp) could serve as an endogenous small molecule exhibiting a wide range of cardiovascular protective effects.

Methods: Zeolitic imidazolate framework-90 (ZIF90) nanoparticles were synthesized and utilized to create a novel delivery nanosystem encapsulated with Sp (CD16/32-ZIF90@Sp). The efficacy of CD16/32-ZIF90@Sp in protecting against AS and ferroptosis was evaluated in ApoE^-/- mice and macrophages, with a focus on assessing potential adverse effects in vivo.

Results: CD16/32-ZIF90@Sp exhibited reliable and stable delivery of Sp within acidic environments and ATP sensitivity. CD16/32-ZIF90@Sp effectively reduced the cytotoxicity of Sp. As is evidenced by in vitro and vivo experiments, CD16/32-ZIF90@Sp showed precise targeting of macrophages within atherosclerotic plaques and ox-LDL-activated macrophages. Furthermore, treatment with CD16/32-ZIF90@Sp effectively attenuated the progression of AS and the ferroptosis of macrophage within plaque in ApoE^-/- mice without causing significant side effects. Mechanistically, we found that CD16/32-ZIF90@Sp inhibited ferroptosis via improving mitochondrial function and upregulating the expression level of GPX4/xCT.

Conclusion: Our study demonstrated that CD16/32-modified ZIF90 nanoparticles could effectively target macrophages within atherosclerotic plaques, leading to the inhibition of atherosclerotic plaque progression in ApoE^-/- mice. These effects were attributed to the enhancement of mitochondrial function and the inhibition of macrophage ferroptosis, with limited side effects.