Macrophage is the key innate immune effector in first-line defense against the pathogens, and can be polarized into different phenotypes to regulate a variety of immunological functions. However, the plasticity of macrophage is extraordinarily recruited, activated, and polarized under pathological conditions, playing paramount roles in occurrence, development, and prognosis of various chronic diseases, such as rheumatoid arthritis (RA), atherosclerosis (AS), and cancer. To this end, macrophage has become an important therapeutic target for etiological treatment of these diseases. Meanwhile, with the development of nanotechnology, various nano-drug delivery systems have been explored to target macrophages for disease modulation, displaying unique advantages to address both pharmaceutic and biopharmaceutic limitations of various drugs. This review aims to summarize the recent progress of macrophage-targeted nanomedicine for chronic diseases immunotherapy. First, the origin, polarization and biological functions of macrophages have been introduced, in which macrophages can differentiate into different phenotypes in response to physiological stimuli to play various immunological roles. Then, the macrophage disorder has been reviewed in related with various chronic diseases, and several representative diseases, including AS, RA, obesity, and cancer, have been discussed in detail to elucidate the pathological contributions of macrophages for disease progress. Next, strategies to regulate macrophages for diseases immunotherapy, such as macrophages depletion, macrophage reprograming, inhibition of macrophage recruitment, are summarized, and particular attention has been paid on bio-functional nanomaterials to engineer macrophages via different mechanisms. Further, methods for macrophage-targeting delivery nanosystems are discussed based on both passive and active targeting approaches. Finally, the perspective is speculated for potential clinical translation, and there still has significant room for the development of novel macrophage-targeting nanomedicine for precise, effective, and biosafe therapy.