Abstract

OCNL@MVs integrate M1 macrophage membrane-mediated cytokine sequestration with non-genetic OSK protein delivery. • The membrane coating provides a receptor-rich decoy interface to reduce macrophage recruitment and M1 polarization. • The OSK-loaded CMC-NLS core enables endosomal escape and nuclear enrichment of OSK proteins in senescent NPCs. • OCNL@MVs attenuate senescence-associated dysfunction and mitigate structural disc degeneration in a rat IVDD model. The structural and functional integrity of the intervertebral disc (IVD) relies on nucleus pulposus cells (NPCs), whose senescence drives intervertebral disc degeneration (IVDD) through impaired self-repair and a senescence-associated secretory phenotype (SASP). SASP fuels macrophage recruitment and M1 polarization, establishing an inflammation-senescence vicious cycle. Although partial reprogramming with pluripotency-associated factors offers rejuvenation potential, clinical translation is impeded by genetic manipulation risks and protein stability challenges. Here, we developed OCNL@MVs, a biomimetic delivery system comprising carboxymethyl chitosan nanoparticles loaded with OSK reprogramming proteins, functionalized with an endosomolytic peptide and nuclear localization signal (NLS), and cloaked in M1 macrophage membranes. OCNL@MVs demonstrated dual functionality: 1) Membrane-derived receptors neutralized inflammatory cytokines and chemokines, reducing macrophage recruitment and M1 polarization; 2) The OSK@CMC-NLS core achieved lysosomal escape and nuclear delivery of OSK proteins, resulting in attenuation of senescence-associated phenotypes and improved proliferative capacity in senescent NPCs. In vivo, OCNL@MVs mitigated disc degeneration by disrupting the inflammatory niche and attenuating senescence-associated dysfunction. This membrane-coated nanoplatform provides a non-genetic protein-delivery strategy with a favorable preliminary biosafety profile, offering therapeutic potential for IVDD and aging-rel