Spatiotemporally Programmable Chaperone‐Mediated Autophagy Activation Disarms the Senescence‐Immunity Axis for Targeted Intervertebral Disc Regeneration

ABSTRACT Intervertebral disc degeneration (IVDD) causes low back pain, yet the causal link between nucleus pulposus cell (NPC) senescence and immune dysregulation remains unclear. Here, we identify that senescent NPCs drive M1 polarization through chaperone‐mediated autophagy (CMA) dysfunction‐dependent NLRP3 inflammasome activation and GSDMD‐mediated HMGB1 secretion, establishing HMGB1 as the core upstream effector of the senescence‐immunity axis. To intercept this cascade, we engineer a reactive oxygen species (ROS)‐responsive hydrogel (TA@HA‐PD‐EVs AR7 ) with differential release kinetics, rapidly releasing tannic acid (TA) for on‐demand antioxidant preconditioning and sustainably delivering AR7‐loaded EVs for CMA reactivation, enabling a functional sequential intervention. This system degrades NLRP3, blocks HMGB1 release, suppresses NPC senescence and SASP, and restores extracellular matrix homeostasis. Leveraging intercellular adhesion molecule 1 (ICAM1) as a surface‐enriched receptor on senescent NPCs, we construct senescence‐targeted EVs for source‐specific HMGB1 blockade. In a rat puncture model, the targeted hydrogel preserves disc height and MRI signal, reduces M1 macrophage infiltration, and attenuates NPC senescence without systemic toxicity. Notably, senescence‐targeted delivery alone achieves efficacy equivalent to dual targeting, confirming HMGB1 as the dominant driver. This work transforms CMA into an actionable checkpoint and provides a precision hydrogel platform that spatiotemporally disrupts the senescence‐immunity vicious cycle, offering a paradigm for IVDD.