Dual-pathological cascade delivery of apoptotic vesicles for targeted therapy in intervertebral disc degeneration

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.