Genetically engineered macrophages co-loaded with CD47 inhibitors effectively restored cardiac efferocytosis, alleviated inflammation, and preserved cardiac function in a mouse model of MI/R injury.
Does intravenous injection of genetically engineered macrophages co-loaded with CD47 inhibitors improve cardiac remodeling and function in a mouse model of myocardial ischemia-reperfusion injury?
Genetically engineered macrophages targeting multiple barriers to efferocytosis offer a novel immune-regulatory therapeutic strategy for improving cardiac remodeling after myocardial ischemia-reperfusion injury.
Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.
Tan et al. (Wed,) conducted a other in Myocardial ischemia-reperfusion (MI/R) injury. Genetically modified macrophages with CCR2 and cleavage-resistant MerTK, surface clicked with liposomal PEP-20 was evaluated on Cardiac efferocytosis, inflammatory response, and cardiac function. Genetically engineered macrophages co-loaded with CD47 inhibitors effectively restored cardiac efferocytosis, alleviated inflammation, and preserved cardiac function in a mouse model of MI/R injury.