Microenvironment‐Responsive Biomimetic Hydrogels Delivering Cistanche Deserticola‐Derived Nanovesicles for Intervertebral Disc Degeneration

Intervertebral disc degeneration (IVDD) is driven by persistent oxidative stress and tissue acidosis, accelerating nucleus pulposus cell (NPC) senescence and extracellular matrix (ECM) degradation. While plant-derived nanovesicles (PDNVs) hold therapeutic promise, rapid clearance and mechanical leakage constrain their translation. Here, natural nanovesicles from Cistanche deserticola (CDNVs) were incorporated into an injectable, microenvironment-responsive hydrogel (HAPOCS@CDNVs) for localized, sustained delivery. Dynamic Schiff base and phenylboronate ester crosslinks provide biomechanical buffering, scavenge reactive oxygen species (ROS), and trigger on-demand CDNV release under acidic and oxidative conditions. Mechanistically, CDNVs alleviate oxidative stress, support mitochondrial function, and inhibit NF-κB activation, thereby suppressing the senescence-associated secretory phenotype (SASP) and preserving ECM homeostasis. In a rat IVDD model, a single intradiscal injection of HAPOCS@CDNVs sustained disc height, preserved tissue hydration, and retarded degeneration over 8 weeks. This platform provides a promising, minimally invasive strategy for disc repair.