The neuro-skeletal crosstalk: Mechanisms, clinical implications, and smart material interventions.

In recent years, the concept of neuro-skeletal crosstalk, highlighting the reciprocal interactions between the nervous and skeletal systems, has opened new avenues for understanding the pathogenesis and intervention strategies of complex diseases. This review summarizes the roles of molecular networks such as neurotransmitters, endocrine factors, immune mediators, and extracellular vesicles in bone metabolism, repair, and neurodegenerative diseases, with an emphasis on recent advances regarding bone-derived signals-including the Piezo1 channel and osteocalcin-in neural regulation. Building on this foundation, we focus on advances in frontier materials such as nanomaterials and hydrogels for modulating the brain-bone microenvironment and facilitating coordinated tissue regeneration, as well as new strategies for targeted drug delivery and immune microenvironment modulation. Empowered by next-generation technologies-including multi-omics, artificial intelligence, and organ-on-a-chip systems-the investigation of the fundamental mechanisms and personalized interventions of the brain-bone axis is entering a new era of opportunity. We hope that this review will provide a theoretical basis and valuable reference for future mechanistic studies and innovation in this interdisciplinary field. Translational potential: By elucidating bidirectional regulatory networks, this review underscores the significant translational potential of targeting the brain-bone axis (BBA) for the treatment of skeletal disorders and neurodegenerative comorbidities. Therapeutic strategies harnessing neurotransmitters (e.g., norepinephrine, serotonin) and neuropeptides (e.g., CGRP) can directly modulate osteoblastic/osteoclastic activity and immune responses, thereby orchestrating fracture repair and metabolic homeostasis. The integration of functional materials-such as stimuli-responsive hydrogels, nanomaterials, and bioelectronic devices-enhances the spatiotemporal precision of signal modulation and facilitates drug delivery across biological barriers, including the blood-brain barrier (BBB). However, challenges regarding low cross-organ targeting efficiency, the complexity of dynamic pathological microenvironments, and physiological discrepancies between animal models and humans necessitate further optimization. Advances in multi-omics analysis, AI-driven network modeling, and intelligent biomimetic delivery systems hold promise for bridging these gaps, offering scalable solutions for clinical translation. This work highlights neuro-skeletal modulation as a transformative dual-targeting strategy for complex diseases, yet its implementation remains contingent upon the refinement of precise intervention technologies and rigorous clinical validation.