Si Yunhui, Dong Shuao, Li Mengsha, Gu Jiaying, Luo Manxuan, Wang Xiaohan, Wang Zhiwei, Li Xiaorong, Zhang Chao
School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, 518107, PR China.
School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou, Guangdong, 510275, PR China.
Mater Today Bio. 2025 May 15;32:101874. doi: 10.1016/j.mtbio.2025.101874. eCollection 2025 Jun.
Repairing critical-sized bone defects represents a major challenge in clinical therapeutics due to inhibited osteogenic differentiation, harsh bone tissue microenvironment, and abnormal inflammatory response. Mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated tremendous regenerative potential in tissue repair. However, the confined therapeutic efficacy, deficient targeting capability, and poor retention rate have rendered MSC-Exos-based cell-free therapies insufficient for clinical bone defect repair. This study prepared curcumin-loaded MSC-Exos (Cur@Exos) based on an endogenous drug delivery approach and encapsulated in bisphosphonate-modified GelMA hydrogel microspheres by microfluidics. The CE@BP-Gel microspheres demonstrated superior biocompatibility and were competent to accelerate biomineralization. The sustained-release Cur@Exos in the composite hydrogel microspheres actively regulated the polarization of RAW264.7 cells toward the regenerative M2 type and inhibited the osteoclastic activity, thereby creating an immune microenvironment suitable for osteogenesis. Meanwhile, the composite hydrogel microspheres can directly support the adhesion, proliferation and osteogenic differentiation of BMSCs and facilitate the migration and angiogenesis of HUVECs. experiments demonstrated that the CE@BP-Gel microspheres significantly accelerated the repair of critical-sized cranial bone defects in SD rats. The targets and mechanisms of action of CE@BP-Gel in bone immune regulation were investigated based on network pharmacology, molecular dynamics simulation and RNA sequencing. It was found that CE@BP-Gel mitigates DNA damage induced by ROS in inflammatory environments. The encapsulated curcumin enhances DNA damage repair by activating the TDP1 enzyme, consequently reducing the expression of inflammatory factors in macrophages. This study demonstrates a promising therapeutic strategy to design an exosome-based drug delivery system for bone defect repair.
修复临界尺寸的骨缺损是临床治疗中的一项重大挑战，这是由于成骨分化受到抑制、骨组织微环境恶劣以及炎症反应异常所致。间充质干细胞衍生的外泌体（MSC-Exos）在组织修复中已展现出巨大的再生潜力。然而，其有限的治疗效果、不足的靶向能力和较差的保留率使得基于MSC-Exos的无细胞疗法不足以用于临床骨缺损修复。本研究基于内源性药物递送方法制备了负载姜黄素的MSC-Exos（Cur@Exos），并通过微流控技术将其封装在双膦酸盐修饰的GelMA水凝胶微球中。CE@BP-Gel微球表现出优异的生物相容性，并能够加速生物矿化。复合水凝胶微球中Cur@Exos的持续释放可积极调节RAW264.7细胞向再生性M2型极化，并抑制破骨细胞活性，从而营造适合成骨的免疫微环境。同时，复合水凝胶微球可直接支持骨髓间充质干细胞的黏附、增殖和成骨分化，并促进人脐静脉内皮细胞的迁移和血管生成。实验表明，CE@BP-Gel微球显著加速了SD大鼠临界尺寸颅骨缺损的修复。基于网络药理学、分子动力学模拟和RNA测序研究了CE@BP-Gel在骨免疫调节中的作用靶点和作用机制。研究发现，CE@BP-Gel可减轻炎症环境中活性氧诱导的DNA损伤。封装的姜黄素通过激活TDP1酶增强DNA损伤修复，从而降低巨噬细胞中炎症因子的表达。本研究展示了一种有前景的治疗策略，即设计一种基于外泌体的药物递送系统用于骨缺损修复。
