Europium-Containing Nanospheres for Treating Ovariectomy-Induced Osteoporosis: Targeted Bone Remodeling and Macrophage Polarization Modulation

Yu-Chi Wang,1,* Meng-Ting Cai,1,* Ming-Hong Chen,2,3 Fu-I Tung,4,5 Mei-Hsiu Chen,6,7 Tse-Ying Liu1 1Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan; 2Division of Neurosurgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan; 3Department of Electrical Engineering, Yuan Ze University, Taoyuan City, 320315, Taiwan; 4Department of Orthopaedics, Yang-Ming Branch, Taipei City Hospital, Taipei, 111024, Taiwan; 5Department of Health and Welfare, College of City Management, University of Taipei, Taipei, 111036, Taiwan; 6Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, 220216, Taiwan; 7Department of Biomedical Engineering, Ming Chuang University, Taoyuan, 333, Taiwan*These authors contributed equally to this workCorrespondence: Tse-Ying Liu; Mei-Hsiu Chen, Email [email protected]; [email protected]: Osteoporosis, characterized by reduced bone mass and structural deterioration, poses a significant healthcare challenge. Traditional treatments, while effective in reducing fracture risks, are often limited by side effects. This study introduces a novel nanocomplex, europium (Eu) ions-doped superparamagnetic iron oxide (SPIO) nanocrystals encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanospheres, abbreviated as SPIO:Eu@PLGA nanospheres, as a potential therapeutic agent for osteoporosis by modulating macrophage polarization, enhancing osteoblast differentiation and inhibiting osteoclastogenesis.Methods: SPIO and SPIO:Eu nanocrystals were synthesized through pyrolysis and encapsulated in PLGA using an emulsification method. To evaluate the impact of SPIO:Eu@PLGA nanospheres on macrophage reprogramming and reactive oxygen species (ROS) production, flow cytometry analysis was conducted. Furthermore, an ovariectomized (OVX) rat model was employed to assess the therapeutic efficacy of SPIO:Eu@PLGA nanospheres in preventing the deterioration of osteoporosis.Results: In vitro, SPIO:Eu@PLGA nanospheres significantly attenuated M1 macrophage activation induced by lipopolysaccharides, promoting a shift towards the M2 phenotype. This action is linked to the modulation of ROS and the NF-κB pathway. Unlike free Eu ions, which do not achieve similar results when not incorporated into the SPIO nanocrystals. SPIO:Eu@PLGA nanospheres enhanced osteoblast differentiation and matrix mineralization while inhibiting RANKL-induced osteoclastogenesis. In vivo studies demonstrated that SPIO:Eu@PLGA nanospheres effectively targeted trabecular bone surfaces in OVX rats under magnetic guidance, preserving their structure and repairing trabecular bone loss by modulating macrophage polarization, thus restoring bone remodeling homeostasis. The study underscores the critical role of Eu doping in boosting the anti-osteoporotic effects of SPIO:Eu@PLGA nanospheres, evident at both cellular and tissue levels in vitro and in vivo.Conclusion: The inclusion of Eu into SPIO matrix suggests a novel approach for developing more effective osteoporosis treatments, particularly for conditions induced by OVX. This research provides essential insights into SPIO:Eu@PLGA nanospheres as an innovative osteoporosis treatment, addressing the limitations of conventional therapies through targeted delivery and macrophage polarization modulation.Keywords: osteoporosis, macrophage polarization, osteoblast, osteoclast, nanocrystals, poly(lactic-co-glycolic acid)