Biomimetic hybrid nanocarriers hitchhike neutrophils for targeted ginsenoside Rc delivery to BMSCs: ameliorating postmenopausal osteoporosis via iron homeostasis regulation

Postmenopausal osteoporosis (PMOP), a prevalent skeletal disorder among postmenopausal women, is hallmarked by heightened fracture susceptibility. Estrogen deficiency in this condition impairs the endogenous antioxidant defense system, triggering iron overload within the bone marrow mesenchymal stem cell (BMSC) niche and disrupting bone metabolic homeostasis. Guided by this mechanistic framework, we focused on ginsenoside Rc (Rc), a bioactive phytochemical endowed with capacities to enhance antioxidant defenses and potential iron-regulating activities. We engineered DT-NPNs/Rc via a pathogen-mimetic strategy, entailing hybridization of bacterial outer membrane vesicles (OMVs) with BMSC-derived membranes for encapsulation of Rc. These nanoconstructs exploit the bone marrow-homing properties of circulating neutrophils for hitchhiking, followed by specific internalization by BMSCs to achieve targeted Rc delivery. Functional assessments revealed that DT-NPNs/Rc mitigates lipid peroxidation through SIRT1/p53 axis, thereby restoring the osteogenic differentiation capacity of BMSCs under iron overload. Notably, in vivo studies confirmed that DT-NPNs/Rc effectively attenuates ovariectomy (OVX)-induced bone loss. Collectively, by overcoming the limitations of conventional delivery systems in targeting, DT-NPNs/Rc offered an innovative, highly efficient, and clinically translatable platform for PMOP treatment. The study developed DT-NPNs/Rc using a pathogen-mimicry strategy, hybridizing bacterial outer membrane vesicles (OMVs) with BMSCs membranes and loading ginsenoside Rc. DT-NPNs hitchhike on circulating neutrophils, leveraging their bone marrow-homing property. The hybrid version with capabilities of penetrating the bone marrow-blood barrier (BMBB) and enhancing BMSCs targeting is a promising research pathway to both optimize the treatment effects and to develop individualized treatments to improve outcomes.