Exosome-mediated macrophage polarization: advances in immunotherapeutic paradigms and mechanisms in skeletal system diseases.

Skeletal system diseases, including osteoarthritis (OA), osteoporosis (OP), and spinal cord injury (SCI), represent a growing global health burden, with chronic low-grade inflammation and macrophage polarization imbalance as shared pathological features. Exosomes have emerged as pivotal mediators of intercellular communication in the bone microenvironment. By delivering diverse bioactive cargoes-including microRNAs, long non-coding RNAs, and functional proteins-they can regulate macrophage phenotypes and modulate the balance between pro-inflammatory and anti-inflammatory states. This review systematically integrates current knowledge on exosome-mediated macrophage polarization in skeletal disorders from a cross-disease perspective. We propose that exosome-based modulation of macrophage phenotypes offers a novel immunotherapeutic paradigm for these conditions. We first outline the biogenesis and cargo-sorting mechanisms of exosomes and highlight the distinct immunoregulatory properties of exosomes derived from different cell sources, including mesenchymal stem cell-derived exosomes (MSC-Exos) that preferentially drive M2 polarization, and M1/M2 macrophage-derived exosomes that respectively sustain pro-or anti-inflammatory feedback loops. We then dissect the key signaling pathways-NF-κB, JAK/STAT, PI3K/AKT/mTOR, and MAPK-through which exosomal components orchestrate macrophage M1/M2 transition at transcriptional, post-transcriptional, and metabolic levels. Importantly, we emphasize recent advances in engineering strategies, such as donor cell preconditioning (hypoxia, cytokines, lipopolysaccharide) and cargo loading (electroporation, 3D culture), which overcome the inherent limitations of natural exosomes and enable precise control of macrophage polarization. By synthesizing evidence from OA, OP, SCI, and other bone-related diseases, we reveal that exosome-based restoration of M1/M2 balance may represent a promising strategy for disease modification. This review not only provides a comprehensive theoretical reference but also highlights forward-looking avenues for precision immunotherapy in musculoskeletal diseases, thereby bridging the gap between basic research and clinical translation.