Atherosclerosis is an inflammatory disease that may cause severe heart disease and stroke.Current pharmacotherapy for atherosclerosis shows limited benefits.In the progression of atherosclerosis,monocyte adhesions and...Atherosclerosis is an inflammatory disease that may cause severe heart disease and stroke.Current pharmacotherapy for atherosclerosis shows limited benefits.In the progression of atherosclerosis,monocyte adhesions and inflammatory macrophages play vital roles.However,precise regulations of inflammatory immune microenvironments in pathological tissues remain challenging.Here,we report an atherosclerotic plaque-targeted selenopeptide nanomedicine for inhibiting atherosclerosis progression by reducing monocyte adhesions and inflammation of macrophages.The targeted nanomedicine has 2.2-fold enhancement in atherosclerotic lesion accumulation.The oxidation-responsibility of selenopeptide enables eliminations of reactive oxygen species and specific release of anti-inflammatory drugs,thereby reducing inflammation responses of macrophages.Notably,we find the oxidative metabolite of selenopeptide,octadecyl selenite,can bind to P-selectin in a high affinity with a dissociation constant of 1.5μM.This in situ generated active seleno-species further inhibit monocyte adhesions for anti-inflammation in synergy.With local regulations of monocyte adhesions and inflammations,the selenopeptide nanomedicine achieves 2.6-fold improvement in atherosclerotic plaque inhibition compared with simvastatin in the atherosclerosis mouse model.Meanwhile,the selenopeptide nanomedicine also displays excellent biological safety in both mice and rhesus monkeys.This study provides a safe and effective platform for regulating inflammatory immune microenvironments for inflammatory diseases such as atherosclerosis.展开更多
基金financially supported by the National Natural Science Foundation of China(Nos.51890892,22175048,22007024,and 21805058)National Key R&D Program of China(No.2018YFE0205400)Beijing Natural Science Foundation(No.2232072).
文摘Atherosclerosis is an inflammatory disease that may cause severe heart disease and stroke.Current pharmacotherapy for atherosclerosis shows limited benefits.In the progression of atherosclerosis,monocyte adhesions and inflammatory macrophages play vital roles.However,precise regulations of inflammatory immune microenvironments in pathological tissues remain challenging.Here,we report an atherosclerotic plaque-targeted selenopeptide nanomedicine for inhibiting atherosclerosis progression by reducing monocyte adhesions and inflammation of macrophages.The targeted nanomedicine has 2.2-fold enhancement in atherosclerotic lesion accumulation.The oxidation-responsibility of selenopeptide enables eliminations of reactive oxygen species and specific release of anti-inflammatory drugs,thereby reducing inflammation responses of macrophages.Notably,we find the oxidative metabolite of selenopeptide,octadecyl selenite,can bind to P-selectin in a high affinity with a dissociation constant of 1.5μM.This in situ generated active seleno-species further inhibit monocyte adhesions for anti-inflammation in synergy.With local regulations of monocyte adhesions and inflammations,the selenopeptide nanomedicine achieves 2.6-fold improvement in atherosclerotic plaque inhibition compared with simvastatin in the atherosclerosis mouse model.Meanwhile,the selenopeptide nanomedicine also displays excellent biological safety in both mice and rhesus monkeys.This study provides a safe and effective platform for regulating inflammatory immune microenvironments for inflammatory diseases such as atherosclerosis.
