Rescuing ACE2‐Deficiency‐Mediated Nucleus Pulposus Senescence and Intervertebral Disc Degeneration by a Nanotopology‐Enhanced RNAi System

Abstract Nucleus pulposus cell (NPC) senescence contributes to intervertebral disc degeneration (IVDD). However, the underlying molecular mechanisms are not fully understood. In this study, it is demonstrated that angiotensin‐converting enzyme 2 (ACE2) counteracted the aging of NPCs and IVDD at the cellular and physiological levels. The expression of ACE2 correlates negatively with the degree of NPC senescence and IVDD. Using both loss‐ and gain‐of‐function mouse models, it is revealed that ACE2 deficiency increased the senescence of NPCs and exacerbated injury‐ or instability‐induced IVDD, whereas ACE2 overexpression counteracted these detrimental effects. Mechanistically, integrated analysis of single‐cell and bulk transcriptomics shows that ACE2 deficiency results in the activation of TGFβ2/Smads signaling pathway and the transcription of Serpine1, ultimately triggering NPC senescence and IVDD. A nanomedical delivery system (virus‐like nanovectors, VNs) composed of nanovectors with a virus‐like surface topology and small interfering RNA targeting Serpine1 (VN‐siSer) is developed. With nanotopology‐enhanced transfection efficiency, RNA‐interfering treatment by VN‐siSer effectively alleviated NPC senescence and IVDD at both the cellular and animal levels. Overall, the data reveal the underlying mechanisms of ACE2 in NPC senescence and IVDD pathogenesis and propose a distinct paradigm of precise nanomedical senescence‐blockade RNAi for IVDD treatment.