Therapeutic strategies based on macrophages and their derivatives: Targeted drug delivery platforms and disease treatment

Targeted drug delivery platforms are designed to enable spatiotemporal precision in transporting therapeutic agents to disease-specific sites, thereby optimizing therapeutic efficacy and mitigating off-target adverse effects. Despite their clinical promise, these platforms remain hindered by substantial translational barriers. Macrophages, with inherent biocompatibility and intrinsic tropism toward inflamed/diseased tissues, are critically involved in diverse pathological processes. Macrophage-based drug delivery systems (MDDSs) have emerged as promising platforms engineered via therapeutic cargo loading onto intact cells, cell-membrane coatings, extracellular vesicles (EVs), or hitchhiking mechanisms. This review delineates existing MDDS platforms, critically analyzing their respective merits and constraints. We further elucidate therapeutic mechanisms and clinical implementations of MDDSs for cancer, atherosclerosis (AS), and central nervous system (CNS) disorders, while establishing a systematic taxonomy of their biomedical applications. Specifically, we highlight the transformative potential of gene-editing technologies (exemplified by chimeric antigen receptor macrophage (CAR-M) therapy and antigen-independent strategies) in innovating next-generation MDDS architectures. We summarize state-of-the-art developments, persisting translational hurdles, and optimization roadmaps for MDDSs, providing a conceptual framework to guide their translational advancement.