Microneedle delivery of CAR-M-like engineered macrophages alleviates intervertebral disc degeneration through enhanced efferocytosis capacity.

Abstract

Macrophages eliminate apoptotic cells produced daily in the body through efferocytosis. Restricted clearance can cause inflammation-related diseases. In intervertebral discs (IVDs), apoptotic nucleus pulposus cells (NPCs) are difficult to effectively remove, and their accumulation can cause changes in the inflammatory microenvironment, disrupt IVD homeostasis, and lead to IVD degeneration (IDD). Here, we present chimeric antigen receptor-M-like engineered macrophages (CAR-eMs) with enhanced efferocytosis capacity for IDD treatment. Macrophages undergo phenotypic transformation and a reduction in phagocytic ability after phagocyting apoptotic NPCs, but their efferocytosis capacity recovers with upregulated brain-specific angiogenesis inhibitor 1 (BAI1) expression. We develop a CAR-eM system with enhanced BAI1 expression and an IVD circular microneedle (MN) delivery system that utilizes arrays of MNs to deliver CAR-eMs into the deep IVD layers, thereby clearing apoptotic NPCs, ameliorating the inflammatory microenvironment, and repairing damaged IVDs. Our study explores the therapeutic potential of CAR-eM efferocytosis for IDD treatment.