Traditional Chinese medicine monomers combined with biomaterials for remodeling the osteoimmune microenvironment to promote bone regeneration

Bone regeneration is a dynamic process governed by interactions among immune responses, bone metabolism, and the local microenvironment. Macrophage phenotypic transitions, oxidative stress, inflammatory signaling, angiogenesis, and the balance between osteogenesis and osteoclastogenesis collectively determine the outcome of bone repair. Traditional Chinese medicine (TCM) monomers have emerged as promising agents for osteoimmune regulation because of their multi-target and multi-pathway activities. Representative monomers, including icariin, baicalin, naringin, quercetin, berberine, curcumin, resveratrol, puerarin, and astragaloside IV, can suppress excessive inflammation by modulating NF-κB- and MAPK-related signaling and reducing pro-inflammatory cytokines. They also alleviate oxidative stress through reactive oxygen species scavenging, regulate macrophage transition toward reparative phenotypes, inhibit osteoclastogenesis through the RANKL/OPG axis and NFATc1 signaling, and promote osteogenic differentiation, matrix mineralization, and angiogenesis through pathways including Wnt/β-catenin, PI3K/Akt, and ERK/MAPK. However, the application of many TCM monomers is limited by poor aqueous solubility, low bioavailability, rapid metabolism, and insufficient retention at bone defect sites. Biomaterial-based delivery systems, including hydrogels, nanocarriers, metal-organic frameworks, layered double hydroxides, electrospun fibers, and three-dimensional printed scaffolds, can improve monomer stability and local retention while enabling sustained, targeted, or stimuli-responsive release. More importantly, these systems are increasingly designed to match drug release with the temporal progression of bone healing, thereby controlling excessive inflammation and oxidative stress during the early phase and subsequently promoting inflammatory resolution, angiogenesis, osteogenesis, and bone remodeling. This review summarizes representative osteoimmunomodulatory TCM monomers, their molecular mechanisms, and their integration with biomaterials, with emphasis on delivery characteristics, immune regulation, and bone-regenerative outcomes. Current challenges, including mismatched release kinetics, excessive reparative macrophage polarization, insufficient monomer standardization, and limited clinical translation, are also discussed. Future studies should prioritize stage-adapted programmed release and microenvironment-responsive delivery to advance TCM monomer–biomaterial systems toward mechanism-driven and precision osteoimmunomodulation.