Zhu Yanrun, Sun Lili, Hou Mingzhuang, Yu Jianfeng, Yu Chenqi, Zhang Zihan, Yang Huilin, Liu Changsheng, Huang Lixin, Jiang Dinghua, Zhang Yijian, Yuan Yuan, Zhu Xuesong
Department of Orthopaedics, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, 215006, China.
Orthopaedic Institute, Medical College, Soochow University, Suzhou, 215000, China.
Bioact Mater. 2025 May 19;51:318-332. doi: 10.1016/j.bioactmat.2025.05.003. eCollection 2025 Sep.
Senescent bone repair faces significant obstacles due to reduced cellular activity and an unfavorable microenvironment, both of which hinder the osteogenic differentiation of bone marrow-derived stem cells (BMSCs) into osteoblasts (OBs) and subsequent bone formation. Current approaches primarily target senescent cell clearance (senolytics) or suppression of the senescence-associated secretory phenotype (senomorphics), neglecting the complex interactions between BMSCs and the osteogenic microenvironment. In this study, a genetically engineered hydrogel incorporating NAD-dependent deacetylase sirtuins 3 (SIRT3)-loaded nano-vectors and poly (glycerol sebacate)-co-poly (ethylene glycol)/polyacrylic acid (PEGS/PAA) was developed as an "inside-out" strategy for bone regeneration. At the intracellular level, BMSC function is restored, and osteogenesis is promoted through genetically enhanced SIRT3 expression. At the extracellular level, carboxyl functional groups chelate iron ions, simulating a hypoxic environment and promoting synergistic interactions between angiogenesis and osteogenesis. The therapeutic effects of the genetically engineered hydrogel in alleviating senescent damage and enhancing osteogenic differentiation were confirmed in both chemically and naturally induced senescence models . Local delivery of the hydrogel significantly increased newly formed bone in rat cranial defects. Mechanistically, the central role of SIRT3 in balancing senescence and osteogenesis, as well as its involvement in bone immune signaling pathways, was elucidated through CRISPR/Cas9-mediated editing in mice and transcriptome sequencing. This work presents a novel paradigm that integrates cellular and microenvironmental factors to enhance bone regeneration, offering new hope for treating age-related bone injuries.
由于细胞活性降低和不利的微环境，衰老骨修复面临重大障碍，这两者均阻碍骨髓来源干细胞（BMSCs）向成骨细胞（OBs）的成骨分化以及随后的骨形成。当前的方法主要针对衰老细胞清除（衰老溶解剂）或衰老相关分泌表型的抑制（衰老形态调节剂），而忽略了BMSCs与成骨微环境之间的复杂相互作用。在本研究中，开发了一种基因工程水凝胶，其包含负载烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰酶Sirtuin 3（SIRT3）的纳米载体和聚（癸二酸甘油酯）-共聚（乙二醇）/聚丙烯酸（PEGS/PAA），作为一种用于骨再生的“由内而外”策略。在细胞内水平，通过基因增强的SIRT3表达恢复BMSC功能并促进成骨。在细胞外水平，羧基官能团螯合铁离子，模拟缺氧环境并促进血管生成与成骨之间的协同相互作用。在化学诱导和自然诱导的衰老模型中均证实了基因工程水凝胶在减轻衰老损伤和增强成骨分化方面的治疗效果。水凝胶的局部递送显著增加了大鼠颅骨缺损处新形成的骨量。从机制上讲，通过小鼠中的CRISPR/Cas9介导的编辑和转录组测序阐明了SIRT3在平衡衰老和成骨中的核心作用及其在骨免疫信号通路中的参与。这项工作提出了一种整合细胞和微环境因素以增强骨再生的新范例，为治疗与年龄相关的骨损伤带来了新希望。
