Engineering CAR‐Macrophages With Advanced Delivery Systems for Tissue Repair

ABSTRACT

Tissue injury and organ dysfunction remain major clinical challenges, as conventional therapies often fail to achieve functional regeneration. Chimeric antigen receptor (CAR) technology endows macrophages with the ability to specifically recognize and clear pathological targets, making CAR‐macrophages (CAR‐M) a promising tool in tissue engineering and regenerative medicine. However, the efficient, safe, and controllable engineering of CAR‐M still depends on advanced chemical delivery systems. This review systematically summarizes five major platforms for CAR‐M engineering, including viral vectors, lipid nanoparticles (LNPs), exosomes/extracellular vesicles, polymeric nanocarriers, and biomaterial scaffolds. Particular emphasis is placed on LNPs optimization strategies, including ionizable lipid design, surface modification, and regulation of physicochemical properties. The influence of delivery systems on macrophage uptake, intracellular trafficking, and polarization is also discussed. This review further highlights recent preclinical applications of CAR‐M therapy in liver fibrosis, cardiac fibrosis, and atherosclerosis. Furthermore, a comparative analysis of CAR‐M with CAR‑T and CAR‑NK therapies is provided, and key challenges, including phenotypic instability, off‑target effects, and limited in vivo persistence, are discussed. Finally, future directions are outlined, including advanced delivery strategies, multi‑target CAR designs, and metabolic modulation, highlighting new opportunities for precision regenerative immunotherapy.