Cardiovascular and cerebrovascular events due to atherosclerosis (AS) are the leading causes of mortality worldwide. Current therapeutic strategies failed to simultaneously target lipid deposition, chronic inflammation, and endothelial dysfunction. Herein, we developed BIFD, a conformationally variable peptide targeting lysophosphatidylcholine (LPC) on oxidized low-density lipoproteins (ox-LDL), which binds ox-LDL to form nanoaggregates, blocking ox-LDL toxicity, reducing inflammation, promoting metabolism/excretion of ox-LDL in macrophage. In addition, both ox-LDL specifically distributed in plaque sites and the targetability of BIFD to ox-LDL enable the BIFD targetability to plaque of AS. Therefore, rapamycin (Rapa), an anti-inflammatory drug, is designed to be encapsulated into BIFD to form Rapa@BIFD nanoparticles (NPs). Rapa@BIFD may target plaque, enhancing accumulation and retention of Rapa@BIFD on the AS lesion. Consequently, Rapa@BIFD demonstrated high efficacy against AS with minimal side effects. In vitro and in vivo studies in apolipoprotein E-knockout murine and canine models revealed that Rapa@BIFD effectively reduced oxidative damage, and inflammatory responses, while promoting lipid metabolism and excretion. Rapa@BIFD mitigated side effects of Rapa, such as hyperlipidemia and splenic toxicity. These findings present a transformative multitarget for AS, combining efficacy with minimal side effects and enhanced clinical translatability.

Advanced Materials, 2026; e21108 https://advanced.onlinelibrary.wiley.com/doi/10.1002/adma.202521108