Therapeutic strategy for exosome-based bone regeneration to osteoporosis: Challenges and potential solutions

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Schematic representation of exosome-based bioengineering strategies for OP therapy. The central portion depicts exosomes derived from various cell sources, including OB, OC, osteocytes, macrophages, and iPSCs. Three major engineering strategies are illustrated: (1) Surface modifications (top-left) enhance targeting and uptake of exosomes via the functionalization of receptors (e.g., RANK, CD44), peptides (DSS6, RGD), and ligands (RANKL, ALD); (2) Cell preconditioning (top-right) under hypoxic or inflammatory conditions promotes osteogenesis and inhibits osteoclastogenesis; and (3) Cargo loading (bottom-left) involves the incorporation of functional RNA species such as siRNAs (e.g., targeting RANK, MMP9), mRNAs (e.g., RUNX2, BMP2), and miRNAs (e.g., miR-21, miR-26a) to stimulate bone formation and reduce resorption. Additionally, immune modification strategies (bottom-right) involving regulatory T cell (Treg) and macrophage-derived exosomes modulate inflammation and suppress osteoclast activity. Together, these approaches offer a versatile and integrated approach to improving the therapeutic efficacy of exosomes in treating bone-related disorders. OP, Osteoporosis; OC, osteoclasts; OB, osteoblasts; iPSCs, induced pluripotent stem cells. • Osteoporosis is marked by weak bones and high susceptibility to the risk of fracture. • Exosomes show strong potential in general bone regeneration. • Translating them to osteoporosis therapy faces unique biological challenges. • Engineering exosomes may overcome barriers like instability and targeting. • Combining exosomes with immune or drug therapies enhances their effect. • Clinical use needs better isolation, standardization, and scale-up methods. Osteoporosis (OP) is a progressive bone disease marked by reduced bone mass and microarchitectural deterioration, thereby increasing fracture risk. Current therapies only partly restore bone quality and often cause side effects with long-term use. Recent studies highlight exosomes, a subtype of extracellular vesicles, as key regulators of bone remodeling with promising regenerative potential. However, their role in osteoporosis remains underexplored. This review aims to investigate how the established role of exosomes in bone regeneration may inform novel therapeutic strategies for osteoporosis. By linking general bone repair mechanisms with osteoporotic pathology, it evaluates the translational potential and limitations of exosome-based interventions. Exosomes derived from mesenchymal stem cells, osteoblasts, osteoclasts, and macrophages regulate bone homeostasis by modulating osteogenesis, osteoclastogenesis, and immune responses. Their regenerative effects in non-osteoporotic settings are well documented. However, challenges such as exosome heterogeneity, rapid clearance, and poor targeting efficiency impede their direct application in osteoporosis. Recent bioengineering approaches, including osteogenic RNA or protein loading and surface modifications for bone targeting, show promise. Moreover, combining exosomes with immunomodulatory or synergistic therapies may further enhance their efficacy. Despite these advances, gaps persist in standardizing isolation techniques, ensuring batch consistency, and scaling up production for clinical use. This review consolidates current knowledge and outlines directions for adapting exosome-based bone regenerative strategies to osteoporosis treatment.