Nanoparticles coated with osteoblast-like cell membranes as curcumin delivery vehicles for targeted postmenopausal osteoporosis therapy

Postmenopausal osteoporosis, driven by estrogen-deficient bone loss, faces therapeutic challenges due to current drug side effects and off-target effects. While curcumin demonstrates dual osteogenic and antiresorptive activity, its clinical translation is hindered by poor aqueous solubility, chemical instability, and photolability. A bone-targeted delivery system using osteoblast-like cell membrane-coated nanoparticles was designed to enhance precision and efficacy for treating osteoporosis. Through systematic database analysis, osteoblast-like cell membrane containing CXCR4 and TNF-α receptors were selected to coat curcumin-loaded PLGA nanoparticles (Cur@NPs), namely OM/Cur@NPs. OM/Cur@NPs and Cur@NPs were injected into ovariectomized (OVX) mice to comparatively assess <i>in vivo</i> bone-targeting. Additionally, leveraging the specific binding capability of TNFR to TNF-α, we evaluated the effects of cell membrane-coated nanoparticles on osteoblasts and osteoclasts formation under TNF-α stimulation <i>in vitro</i>. We further evaluated the anti-osteoporotic efficacy of OM/Cur@NPs <i>in vivo</i> by micro-CT analysis (BMD, Tb.BV/TV, Tb.N, Tb.Th, Tb.Sp) and histological examination of bone formation and resorption. The OM/Cur@NPs group exhibited higher bone accumulation compared to Cur@NPs in OVX mice. Notably, these biomimetic nanoparticles neutralized TNF-α, thereby enhancing osteoblastic functions, while attenuating the synergistic pro-osteoclastogenic effects of TNF-α and RANKL. <i>In vivo</i> studies demonstrated that the OM/Cur@NPs-treated group showed superior radiographic bone parameters (BMD, Tb.BV/TV, Tb.N, Tb.Th, Tb.Sp) compared to other experimental groups. Furthermore, histological examination revealed the dual efficacy of OM/Cur@NPs in enhancing bone formation while inhibiting bone resorption in osteoporotic mice. This dual-functional platform couples targeted drug delivery with inflammatory microenvironment modulation and holds promise for metabolic bone disorders.