Conditional sequential delivery of ginkgetin and rapamycin orchestrates inflammation and autophagy to alleviate intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a multifaceted and complex condition primarily driven by excessive inflammation, degradation of the extracellular matrix (ECM), and dysfunction of nucleus pulposus cells (NPCs). Despite extensive exploration of various therapeutic agents targeting IVDD, their efficacy remains disappointingly limited. This study underscores the efficacy of ginkgetin (GK), a natural bioflavonoid with potent anti-inflammatory properties, in mitigating inflammation as well as ECM degradation and NPC dysfunction triggered by interleukin-1β (IL-1β). However, GK alone cannot fully address the persistent obstruction in autophagic flux induced by IL-1β. To overcome this limitation, an innovative MMP13-responsive nanoplatform was developed, orchestrating the sequential delivery of GK and rapamycin (RA), targeting distinct phases of IVDD progression. In this design, GK is progressively released from exosomes during the initial phase, while RA is released from mesoporous silica nanoparticles during the mid-phase to enhance autophagic flux. This staged release approach leverages the strengths of both agents, addressing inflammation and restoring autophagy more effectively. In vivo experiments confirmed the substantial therapeutic benefits of this staggered delivery strategy in IVDD. The engineered MMP13-responsive nanoplatform represents a significant advancement in controlled, sequential drug delivery systems, offering a promising therapeutic avenue to effectively regulate inflammation and autophagy, thereby ameliorating IVDD.