Regenerative bone-targeted nanoparticles modulate osteoclast function.

Osteoclasts are vital for maintaining bone health. Indeed, dysregulated osteoclast activity is linked to pathological conditions such as Paget's disease, osteoporosis, and impaired fracture healing. Despite their importance in bone regeneration, few biomaterial-based strategies have been developed to alter osteoclast recruitment, differentiation, activity, or crosstalk with osteoblasts. To improve bone healing, we previously developed a drug delivery system (DDS) that expedites fracture repair. The DDS is composed of poly(styrene-alt-maleic anhydride)-block-poly(styrene) (PSMA-b-PS) functionalized with a peptide with inherent specificity to tartrate-resistant acid phosphatase (TRAP), a protein deposited by osteoclasts after bone injury (fracture, non-union, etc.). When loaded with a Wnt/β-catenin agonist (AR28), the TRAP binding peptide (TBP)-functionalized nanoparticle (TBP-NPAR28) enhanced fracture healing by promoting pro-regenerative polarization of macrophages, enhancing osteogenic differentiation, and expediting fracture healing. Given their crucial role in bone healing and proximity during fracture repair, here we investigated the impact of NP on osteoclasts. Murine bone marrow-derived osteoclasts treated with NPs exhibited decreased osteoclastogenesis due to downregulation of key osteoclast genes (NFATc, cFOS, and CTSK) and function as assessed by reduced bone resorption capacity. The inhibition of osteoclastogenesis and the reduction in osteoclast function demonstrated here suggest that TBP-NPAR28 is a promising approach for improving bone regeneration by combining osteoclast inhibition with its previously reported effects on bone formation. This offers new therapeutic strategies for bone diseases characterized by dysregulation of bone homeostasis.