Synthetic nanoparticles functionalized with cell membrane-mimicking, bone-targeting, and ROS-controlled release agents for osteoporosis treatment

Weijun Zhang; Ye Zhang; Zhengan Hao; Pengjie Yao; Jinwu Bai; Hongyu Chen; Xiaoyong Wu; Yuliang Zhong; Deting Xue

doi:10.1016/j.jconrel.2024.12.017

Synthetic nanoparticles functionalized with cell membrane-mimicking, bone-targeting, and ROS-controlled release agents for osteoporosis treatment

J Control Release. 2024 Dec 18:378:306-319. doi: 10.1016/j.jconrel.2024.12.017. Online ahead of print.

Authors

Weijun Zhang¹, Ye Zhang¹, Zhengan Hao¹, Pengjie Yao¹, Jinwu Bai², Hongyu Chen¹, Xiaoyong Wu¹, Yuliang Zhong¹, Deting Xue³

Affiliations

¹ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China; Clinical Research Center of Motor System Disease of Zhejiang Province, PR China.
² Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, China.
³ Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China; Clinical Research Center of Motor System Disease of Zhejiang Province, PR China. Electronic address: blueskine@zju.edu.cn.

PMID: 39694070
DOI: 10.1016/j.jconrel.2024.12.017

Abstract

Postmenopausal osteoporosis is a common degenerative disease, with suboptimal clinical outcomes. The targets of current therapeutic agents are both nonspecific and diverse. We synthesized a novel nanoparticle (NP), ALN@BMSCM@PLGA-TK-PEG-SS31. After intravenous injection, the NP evaded immune phagocytosis, targeted bone tissue, and efficiently downregulated bone reactive oxygen species (ROS) generation. The core PLGA-TK-PEG-SS31 NP was ∼100 nm in diameter. The TK chemical bond breaks on exposure to ROS, releasing the novel mitochondrion-targeting peptide SS31. Outer bone marrow mesenchymal stem cell membranes (BMSCMs) were used to coat the NP with surface proteins to ensure membrane functionality. The circulation time was prolonged and immune phagocytosis was evaded. Embedding the DSPE-PEG-ALN lipid within the cell membrane enhanced the bone-targeting ability of the NP. Our results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 exerted dual effects on bone tissue in vitro, significantly inhibiting RANKL-induced osteoclastogenesis in the presence of H₂O₂ and promoting osteogenic differentiation in BMSCs. In a mouse model of ovariectomy-induced osteoporosis, ALN@BMSCM@PLGA-TK-PEG-SS31 significantly ameliorated oxidative stress and increased bone mass with no notable systemic side effects. These results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 is a promising treatment for osteoporosis.

Keywords: BMSCs; Bone targeting; Membranes; Osteoporosis; ROS; SS31.