Macrophages are natural immune cells that have been studied and engineered for disease treatment. They are suitable as drug carriers due to their biocompatibility, long circulation, and ability to home to inflamed areas. Macrophages can be polarized to different phenotypes, making them effective for treating inflammatory diseases and tumors. However, challenges remain in improving therapeutic effects and clinical applications. This review discusses key challenges in macrophage-based drug delivery, including macrophage source selection, drug loading, phenotype maintenance, and drug release at target sites. Strategies to address these challenges are also presented. Macrophages can be sourced from various origins, such as bone marrow-derived macrophages (BMDMs), primary macrophages, and cell lines like RAW264.7. Drug loading strategies include phagocytosis of particles or conjugation to the cell membrane. Challenges include low drug loading capacity, rapid conversion of macrophages to harmful states, and uncontrolled drug release. Strategies to improve drug loading include optimizing particle properties and using nanocapsules. Macrophage phenotype modulation is also crucial, as their plasticity can lead to therapeutic failure. Strategies to sustain macrophage phenotypes include phagocytosis of microparticles, surface modification, and gene modification. These approaches aim to enhance the effectiveness of macrophage-based therapies in clinical applications.Macrophages are natural immune cells that have been studied and engineered for disease treatment. They are suitable as drug carriers due to their biocompatibility, long circulation, and ability to home to inflamed areas. Macrophages can be polarized to different phenotypes, making them effective for treating inflammatory diseases and tumors. However, challenges remain in improving therapeutic effects and clinical applications. This review discusses key challenges in macrophage-based drug delivery, including macrophage source selection, drug loading, phenotype maintenance, and drug release at target sites. Strategies to address these challenges are also presented. Macrophages can be sourced from various origins, such as bone marrow-derived macrophages (BMDMs), primary macrophages, and cell lines like RAW264.7. Drug loading strategies include phagocytosis of particles or conjugation to the cell membrane. Challenges include low drug loading capacity, rapid conversion of macrophages to harmful states, and uncontrolled drug release. Strategies to improve drug loading include optimizing particle properties and using nanocapsules. Macrophage phenotype modulation is also crucial, as their plasticity can lead to therapeutic failure. Strategies to sustain macrophage phenotypes include phagocytosis of microparticles, surface modification, and gene modification. These approaches aim to enhance the effectiveness of macrophage-based therapies in clinical applications.