Abstract: Osteoporosis is a systemic metabolic bone disease. Its onset can significantly reduce the quality of life of patients and impose a heavy socioeconomic burden. In patients, the structure of bone marrow microvessels is damaged, and the coupling balance between bone resorption and bone formation is disrupted, leading to a long-term low-grade chronic inflammatory state in the bone microenvironment. The essence of this disease involves the interaction between immune cells and bone cells. In recent years, nanomaterials have developed rapidly in the field of bone tissue engineering and achieved remarkable results. However, the interaction between biomaterials and the immune system involves multi-level immune responses, and this complexity poses challenges for the long-term biocompatibility assessment and clinical translation of these materials. Modified nanomaterials can improve bone metabolism by regulating the immune microenvironment and targeting immune cells, suggesting that they are expected to become a new strategy for intervening in the course of osteoporosis. This article reviewed the key events by which nanomaterials regulate bone regeneration through mediating immune responses and elucidated the "nanomaterials-immunomodulation-bone metabolism" interaction network, aiming to provide a potential interdisciplinary new perspective for the treatment of osteoporosis.