Folate-modified biomimetic nanovesicles loaded with a PU.1 inhibitor alleviate atherosclerosis by suppressing inflammation.

Atherosclerosis is a chronic inflammatory disease affecting arterial walls and remains a leading cause of morbidity and mortality worldwide. While anti-inflammatory therapy is widely recognized as a critical component in the management of atherosclerosis, current treatments are often limited by adverse effects and suboptimal efficacy. Membrane-derived nanovesicles have demonstrated excellent biocompatibility and prolonged circulation times, making them effective drug delivery carriers. However, their targeting capabilities remain limited, as only a small fraction of transmembrane proteins possesses intrinsic targeting functions. To overcome these limitations and leverage the targeting capability of folate in inflammatory disease, we designed biomimetic nanovesicles modified with folate by covalently conjugating folate-C(6)-PEG(4)-NHS to nanovesicles under physiological conditions enabling efficient drug delivery to atherosclerotic plaques. Meanwhile we also identified the PU.1 inhibitor DB1976 as an anti-inflammatory target for the treatment of atherosclerosis. Mechanistically, DB1976 suppresses inflammation by inhibiting the IL-1β/NF-κB signaling pathway, reducing reactive oxygen species (ROS) levels, and decreasing apoptosis rates. Folate-modified biomimetic nanovesicles loaded with DB1976 achieved promising therapeutic outcomes. In summary, folate-modified macrophage biomimetic nanovesicles loaded with a PU.1 inhibitor effectively alleviate atherosclerosis by targeting inflammation in atherosclerotic plaques, highlighting their potential as a promising therapeutic strategy for atherosclerosis treatment.