Time-Controlled Dual Targeting to Program Systemic and Intercellular Transfer of Therapeutic Effects

Abstract

Cell–cell communication serves as a foundation for intercellular therapeutic hand-over. Despite the commonsense level of understanding, no clear projection has been made to prove the mechanism. Here, the hand-over of aspirin from monocytes to inflamed cells is validated using a high-resolution time series of 3D imaging in vitro, with in vivo confirmation. Notably, caveolin is identified to play a major role in mediating the hand-over using cell receptors by super-resolution microscopy, which is induced by the overexpression of caveolin upon inflammation. When aspirin-liposomes are loaded into splenic monocytes, they naturally target inflamed sites efficiently because spleen is a major site of liposomal clearance from the body, in addition to monocyte residence to leave toward inflammatory signals. The delivery efficiency and anti-inflammatory effects of hand-over through intravenous injection are superior to those of oral injection of soluble aspirin, as confirmed in the ischemic hindlimb and fatty liver of mice (targeted therapy). These results are also agreed by the antiplatelet effect in mouse blood over 7 days (prolonged therapy) and the combination of these therapeutic actions effectively rescues the atherosclerotic carotid arteries of mice. This study demonstrates the working mechanism of the hand-over, suggesting a translational strategy to improve intercellular delivery.