An annulus fibrosus anchored nanovector reprograms osteopontin driven macrophages in preclinical disc degeneration models.

Intervertebral disc degeneration is a major cause of low back pain and is associated with inflammatory macrophages that promote annulus fibrosus degeneration via osteopontin signaling. 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. These findings support an inflammation responsive immunomodulatory approach for disc repair in preclinical models.