The mechano-immune-vesicle regulatory circuit: a systems framework for bone homeostasis and regeneration.

Bone remodeling is a mechanically adaptive process that integrates physical loading with immune regulation during homeostasis, repair, and disease. However, the traditional view fails to fully explain how mechanical and immune signals are coordinated across cellular compartments. Emerging evidence indicates that mechanical forces, immune responses, and extracellular vesicles (EVs) function as an integrated communication system rather than independent regulators. Here, we propose a systems-level framework termed the "mechano-immune-vesicle regulatory circuit". In this framework, biophysical cues regulate EV biogenesis and selective cargo sorting through mechanotransduction pathways. These mechanically primed EVs then serve as communication vectors that reprogram osteoimmune responses, specifically by directing macrophage polarization, adaptive immunity, and bone-resident cell differentiation. The resulting immune output feeds back to reshape EV signaling and mechanosensitivity, suggesting a closed regulatory circuit that governs bone remodeling. By synthesizing advances in mechanobiology, osteoimmunology and EV biology, this review reframes bone remodeling as a mechano-immune-vesicle regulatory circuit rather than as a collection of parallel pathways. We further discuss how this framework may guide the design of mechano-responsive biomaterials and engineered EV-based therapies with spatiotemporal control over inflammation and bone regeneration. This conceptual integration provides a mechanistic basis for understanding bone diseases and for developing next-generation regenerative strategies.