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 1.5 µM. 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.

动脉粥样硬化是一种炎症性疾病，可能导致严重的心脏病和中风。目前治疗动脉粥样硬化的药物治疗效果有限。在动脉粥样硬化的进展中，单核细胞粘附和炎症巨噬细胞起着至关重要的作用。然而，病理组织中炎症免疫微环境的精确调节仍然具有挑战性。在这里，我们报道了一种针对动脉粥样硬化斑块的硒肽纳米药物，通过减少单核细胞粘附和巨噬细胞炎症来抑制动脉粥样硬化进展。靶向纳米药物可将动脉粥样硬化病变的积累增强 2.2 倍。硒肽的氧化作用能够消除活性氧并特异性释放抗炎药物，从而减少巨噬细胞的炎症反应。值得注意的是，我们发现硒肽的氧化代谢物十八烷基亚硒酸盐可以以高亲和力与 P-选择素结合，解离常数为 1.5 µM。原位产生的活性硒类进一步抑制单核细胞粘附，从而协同抗炎。通过对单核细胞粘附和炎症的局部调节，在动脉粥样硬化小鼠模型中，与辛伐他汀相比，硒肽纳米药物的动脉粥样硬化斑块抑制效果提高了2.6倍。同时，硒肽纳米药物在小鼠和恒河猴中也表现出优异的生物安全性。该研究为调节动脉粥样硬化等炎症性疾病的炎症免疫微环境提供了一个安全有效的平台。