Work

Bone homeostasis regulation by in vivo generation of osteoclast-derived apoptotic bodies using targeted self-assembly

Year: 2025

Type: article

Abstract: Osteoporosis therapies remain limited by non-specific osteoclast inhibition, which disrupts physiological bone remodeling and increases fracture risk. Here we show that selectively targeting mature osteoclasts via enzyme-responsive nanoparticles could eliminate pathological bone resorption while generating apoptotic bodies (ABs) to promote regeneration. We design OsteoSAVE, a peptide-based nanoparticle integrating a cathepsin K (CTSK)-cleavable linker, a bone-targeting motif, and a self-assembling biphenyl core. Upon CTSK-mediated hydrolysis, OsteoSAVE transforms into nanofibers within osteoclast lysosomes, inducing apoptosis and releasing ABs enriched with PDGF-BB. Mechanistic studies confirm CTSK-selective cleavage and charge-driven cellular specificity. In ovariectomized mice, OsteoSAVE restores bone density by coupling osteoclast elimination with ABs-mediated osteogenesis via PI3K/AKT activation in mesenchymal stem cells. This work establishes enzyme-triggered supramolecular self-assembly as a paradigm for dual-action therapies that recalibrate bone homeostasis without disrupting physiological processes. Triggering the natural repair processes in the body has huge potential in tissue regeneration. Here, the authors develop a bone-targeted nanoparticle that selectively eliminates osteoclasts and generates pro-regenerative apoptotic bodies, restoring bone density and treating osteoporosis.

Source: Nature Communications

DOI: 10.1038/s41467-025-66791-9