Macrophages, as natural immune cells and antigen-presenting cells, have been extensively studied and engineered for treating human diseases. Their biological characteristics, such as excellent biocompatibility, long circulation time, intrinsic inflammatory homing, and phagocytosis, make them well-suited for drug delivery. The high plasticity and easy re-education polarization of macrophages also facilitate their use in therapeutic applications for inflammatory diseases or tumors. However, several challenges currently hinder the improvement of therapeutic effects and clinical application. This article focuses on the main challenges of utilizing macrophage-based drug delivery, including the selection of macrophage sources, drug loading, maintenance of macrophage phenotypes, and drug migration and release at target sites. Corresponding strategies and insights related to these challenges are described. Finally, the authors provide perspectives on the shortcomings on the road to clinical translation and production. Macrophages are natural immune cells derived from circulating monocytes and are widely distributed in all tissues. They play crucial roles in homeostasis, immune surveillance, tissue repair, and inflammation resolution. During tissue injury, infection, or inflammation, monocytes migrate to tissues and differentiate into tissue-resident macrophages. Macrophages exhibit high plasticity, switching between phenotypes to adapt to different environments. This plasticity gives them potential for cell therapy, aiming to replace local macrophage populations with engineered exogenous cells. The selection of macrophage sources is crucial for therapeutic applications. Bone marrow-derived macrophages (BMDMs) are commonly used due to their homogeneity, long lifespan, and ability to be transfected. However, BMDMs may have phenotypic and functional instability in vivo. Peritoneal macrophages (PMs) and spleen macrophages (SPMs) are also used, with PMs showing more stable functional and phenotypic characteristics compared to BMDMs. The choice of macrophage source depends on the pathological characteristics of the disease and the natural properties and functions of different macrophage sources. Macrophages are large cells with a diameter of 25 μm, providing sufficient space for drug loading. Drugs can be loaded into the cytoplasmic space through phagocytosis or attached to the cell membrane. Phagocytosis of drugs or drug-loaded particles into the cytoplasm offers advantages such as extended circulation time and controlled release. However, the low drug loading capacity of cells remains a drawback. Loading drugs onto the surface of macrophages is another approach, but it may affect cell membrane function and reduce drug loadings. Macrophages can be polarized into M1 or M2 phenotypes, each with distinct functional characteristics. M1 macrophages are pro-inflammatory and anti-tumor, while M2 macrophages are anti-inflammatory and associated with tumor growth. Maintaining the therapeutic phenotype of macrophages is crucial for effective therapy. Strategies to sustain macrophage phenotypes includeMacrophages, as natural immune cells and antigen-presenting cells, have been extensively studied and engineered for treating human diseases. Their biological characteristics, such as excellent biocompatibility, long circulation time, intrinsic inflammatory homing, and phagocytosis, make them well-suited for drug delivery. The high plasticity and easy re-education polarization of macrophages also facilitate their use in therapeutic applications for inflammatory diseases or tumors. However, several challenges currently hinder the improvement of therapeutic effects and clinical application. This article focuses on the main challenges of utilizing macrophage-based drug delivery, including the selection of macrophage sources, drug loading, maintenance of macrophage phenotypes, and drug migration and release at target sites. Corresponding strategies and insights related to these challenges are described. Finally, the authors provide perspectives on the shortcomings on the road to clinical translation and production. Macrophages are natural immune cells derived from circulating monocytes and are widely distributed in all tissues. They play crucial roles in homeostasis, immune surveillance, tissue repair, and inflammation resolution. During tissue injury, infection, or inflammation, monocytes migrate to tissues and differentiate into tissue-resident macrophages. Macrophages exhibit high plasticity, switching between phenotypes to adapt to different environments. This plasticity gives them potential for cell therapy, aiming to replace local macrophage populations with engineered exogenous cells. The selection of macrophage sources is crucial for therapeutic applications. Bone marrow-derived macrophages (BMDMs) are commonly used due to their homogeneity, long lifespan, and ability to be transfected. However, BMDMs may have phenotypic and functional instability in vivo. Peritoneal macrophages (PMs) and spleen macrophages (SPMs) are also used, with PMs showing more stable functional and phenotypic characteristics compared to BMDMs. The choice of macrophage source depends on the pathological characteristics of the disease and the natural properties and functions of different macrophage sources. Macrophages are large cells with a diameter of 25 μm, providing sufficient space for drug loading. Drugs can be loaded into the cytoplasmic space through phagocytosis or attached to the cell membrane. Phagocytosis of drugs or drug-loaded particles into the cytoplasm offers advantages such as extended circulation time and controlled release. However, the low drug loading capacity of cells remains a drawback. Loading drugs onto the surface of macrophages is another approach, but it may affect cell membrane function and reduce drug loadings. Macrophages can be polarized into M1 or M2 phenotypes, each with distinct functional characteristics. M1 macrophages are pro-inflammatory and anti-tumor, while M2 macrophages are anti-inflammatory and associated with tumor growth. Maintaining the therapeutic phenotype of macrophages is crucial for effective therapy. Strategies to sustain macrophage phenotypes include