Department of Orthopedics, Medical 3D Printing Center, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, Jiangsu, China.
Department of Orthopedics, Medical 3D Printing Center, The First Affiliated Hospital of Soochow University, 188 Shizi Road, Suzhou, 215006, Jiangsu, China; Department of Orthopedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China.
Biomaterials. 2023 Nov;302:122352. doi: 10.1016/j.biomaterials.2023.122352. Epub 2023 Oct 13.
Osteoporosis is a degenerative disease affecting millions of elderly people globally and increases the risk of bone fractures due to the reduced bone density. Drugs are normally prescribed to treat osteoporosis, especially after surgical treatment of osteoporotic fractures. However, many anti-osteoporotic drugs produce deleterious side effects. The recent development of gene therapy utilizing oligonucleotides (ONs) has spurred the development of new therapies for osteoporosis. Nevertheless, most ONs lack the capability of cell penetration and lysosome escape and hence, intracellular delivery of ON remains a challenge. Herein, a novel strategy is demonstrated to efficiently deliver ON to cells by combining ON with the cell-penetrating peptide (CPP) via the bio-orthogonal click reaction. Several dopamine (DOPA) groups are also introduced into the fabricated peptide to scavenge intracellular reactive oxygen species (ROS). Owing to favorable properties such as good cytocompatibility, cell penetration, lysosome escape, ROS scavenging, and osteoclastogenesis suppression, the hybrid CPP-DOPA-ON peptide improves the osteoporotic conditions significantly in vivo even when bone implants are involved. This strategy has great potential in the treatment of osteoporosis and potentially broadens the scope of gene therapy.
骨质疏松症是一种全球性的退行性疾病，影响着数以百万计的老年人，由于骨密度降低，增加了骨折的风险。通常开药物来治疗骨质疏松症，尤其是在骨质疏松性骨折的手术后。然而，许多抗骨质疏松药物会产生有害的副作用。最近利用寡核苷酸（ONs）的基因治疗的发展，刺激了骨质疏松症新疗法的发展。然而，大多数 ONs 缺乏细胞穿透和溶酶体逃逸的能力，因此，ON 的细胞内传递仍然是一个挑战。本文展示了一种通过生物正交点击反应将 ON 与穿透肽（CPP）结合来有效递送到细胞的新策略。还引入了几个多巴胺（DOPA）基团到所制备的肽中，以清除细胞内的活性氧（ROS）。由于具有良好的细胞相容性、细胞穿透性、溶酶体逃逸性、ROS 清除和破骨细胞生成抑制等特性，该混合 CPP-DOPA-ON 肽即使在涉及骨植入物的情况下，也能显著改善体内的骨质疏松症状况。该策略在骨质疏松症的治疗中具有很大的潜力，并且可能拓宽了基因治疗的范围。
