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Here we report an annulus fibrosus anchored nanovector carrying small interfering RNA targeting osteopontin. The nanovector first binds annulus fibrosus cells via a targeting peptide and is subsequently activated by reactive oxygen species in inflammatory microenvironments to release macrophage targeted hybrid nanovesicles. This sequential design enables local retention in disc tissue and subsequent delivery to osteopontin expressing macrophages. Using human single cell transcriptomic analysis, in vitro macrophage and annulus fibrosus cell coculture assays, mouse macrophage depletion and infiltration models, and rat disc injury models, we show that this strategy reduces pro inflammatory macrophage polarization, preserves extracellular matrix integrity, and improves disc structure. 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