Chen Wei, Zhao Tianyuan, Ren Yiming, Huang Wenzhe, Xia Jiyuan, Hu Zhenxin, Chen Libo, Li Hao, Zhang Qi, Wang Han, Cui Penglei, Guo Quanyi, He Da
Department of Spine, Peking University Fourth School of Clinical Medicine, Beijing, 100035, China.
Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, China.
Mater Today Bio. 2025 Aug 15;34:102200. doi: 10.1016/j.mtbio.2025.102200. eCollection 2025 Oct.
Achieving effective drug delivery and therapeutic efficacy poses significant challenges in intervertebral disc degeneration (IDD). Here, we developed a dual-pathological cascade delivery system utilizing therapeutic mesenchymal stem cell-derived apoptotic vesicles (ApoVs). These vesicles are engineered with MMP13-responsive cell-penetrating peptides (MR-ApoVs) for targeted modulation of senescence. A reactive oxygen species (ROS)-responsive hydrogel incorporating CD44 aptamers (Apt-Gel) was developed to provide high-affinity retention and spatiotemporal controlled release of MR-ApoVs. In this system, MR-ApoV release is first triggered by hydrogel degradation in response to elevated ROS levels. Subsequently, the MMP13-responsive peptides on MR-ApoVs are activated to enhance their internalization into senescent nucleus pulposus (NP) cells, thereby achieving a sequential response to pathological signals within the degenerative disc microenvironment. In a rat model of IDD, MR-ApoV@Apt-Gel effectively attenuated NP cell senescence, restored extracellular matrix homeostasis, preserved disc hydration, and maintained intervertebral disc height. This dual-pathological cascade-responsive strategy represents a promising therapeutic approach for IDD treatment.
在椎间盘退变（IDD）中，实现有效的药物递送和治疗效果面临重大挑战。在此，我们开发了一种利用治疗性间充质干细胞衍生的凋亡小泡（ApoVs）的双病理级联递送系统。这些小泡经基质金属蛋白酶13（MMP13）响应性细胞穿透肽工程改造（MR-ApoVs），用于靶向调节衰老。开发了一种结合CD44适体的活性氧（ROS）响应水凝胶（Apt-Gel），以实现MR-ApoVs的高亲和力保留和时空控制释放。在该系统中，MR-ApoV的释放首先由水凝胶响应升高的ROS水平降解触发。随后，MR-ApoVs上的MMP13响应肽被激活，以增强它们内化进入衰老的髓核（NP）细胞，从而实现对退变椎间盘微环境中病理信号的顺序响应。在IDD大鼠模型中，MR-ApoV@Apt-Gel有效减轻NP细胞衰老，恢复细胞外基质稳态，保持椎间盘水合作用，并维持椎间盘高度。这种双病理级联响应策略代表了一种有前景的IDD治疗方法。
