Abstract
Stem cell therapy is a promising strategy for cardiac repair. However, clinical efficacy is hampered by poor cell engraftment and the elusive repair mechanisms of the transplanted stem cells. The lung is a reservoir of hematopoietic stem cells (HSCs) and a major biogenesis site for platelets. A strategy is sought to redirect lung resident stem cells to the injured heart for therapeutic repair after myocardial infarction (MI). To achieve this goal, CD34-CD42b platelet-targeting bispecific antibodies (PT-BsAbs) are designed to simultaneously recognize HSCs (via CD34) and platelets (via CD42b). After inhalation delivery, PT-BsAbs reach the lungs and conjoined HSCs and platelets. Due to the innate injury-finding ability of platelets, PT-BsAbs guide lung HSCs to the injured heart after MI. The redirected HSCs promote endogenous repair, leading to increased cardiac function. The repair mechanism involves angiomyogenesis and inflammation modulation. In addition, the inhalation route is superior to the intravenous route to deliver PT-BsAbs in terms of the HSCs' homing ability and therapeutic benefits. This work demonstrates that this novel inhalable antibody therapy, which harnesses platelets derived from the lungs, contributes to potent stem cell redirection and heart repair. This strategy is safe and effective in a mouse model of MI.