Enhancing CAR Macrophage Efferocytosis Via Surface Engineered Lipid Nanoparticles Targeting LXR Signaling

Abstract

The removal of dying cells, or efferocytosis, is an indispensable part of resolving inflammation. However, the inflammatory microenvironment of the atherosclerotic plaque frequently affects the biology of both apoptotic cells and resident phagocytes, rendering efferocytosis dysfunctional. To overcome this problem, we developed a chimeric antigen receptor (CAR) macrophage that could target and engulf phagocytosis‐resistant apoptotic cells expressing CD47. In both normal and inflammatory circumstances, CAR macrophages exhibited activity equivalent to antibody blockage. The surface of CAR macrophages was modified with Reactive Oxygen Species (ROS)‐responsive therapeutic nanoparticles targeting the liver X receptor pathway to improve their cell effector activities. The combination of CAR and nanoparticle engineering activated lipid efflux pumps, enhanced cell debris clearance, and reduced inflammation. We further suggest that the undifferentiated CAR‐Ms can transmigrate within a mico‐fabricated vessel system. We also show our CAR macrophage can act as a Chimeric Switch Receptor (CSR) to withstand the immunosuppressive inflammatory environments through enhanced stimulation via CD47‐SIRPα interaction. Based on our current understanding, our developed platform has the potential to contribute to the advancement of next‐generation cardiovascular disease therapies, but further studies, especially in vivo experiments, might be needed to assess its efficacy and safety fully.This article is protected by copyright. All rights reserved

Macrophage plasticity: signaling pathways, tissue repair, and regeneration

“… 205 As such, targeting LXR signaling has emerged as a potential therapeutic strategy for modulating macrophage polarization and function in inflammatory diseases. 206 …”