Apoptotic extracellular vesicles act as master regulators of the bone healing niche.

Apoptotic extracellular vesicles (ApoEVs), natural bilayer nanoparticles released during programmed cell death, have emerged as pivotal regulators and promising therapeutic agents for bone regeneration. They function as innate multimodal signaling entities, expertly coordinating the complex cellular interplay between osteogenesis, angiogenesis, innervation, and immunomodulation required for successful bone healing. This review systematically outlines the biogenesis, isolation, and fundamental mechanisms by which ApoEVs orchestrate the bone healing niche. We further explore their dual role in bone homeostasis and pathology, highlighting applications in treating osteoporosis and osteoarthritis, while acknowledging potential negative effects from specific cellular origins. The significant promise of ApoEVs is being unlocked through innovative engineering strategies to enhance their therapeutic efficacy and specificity. Critically, we discuss how emerging artificial intelligence (AI) tools are poised to overcome major translational hurdles. Despite the challenges in standardization and scalable production, the convergence of ApoEV biology and AI-driven design positions them as a transformative next-generation, cell-free platform for treating intractable bone and joint disorders.