GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE289nnn/GSE289741/primaryOK200TranscriptomicsRattus norvegicusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE289741GEOGSEfalseROS-responsive OMV-liposome hybrid targets macrophages and annulus fibrosus cells to modulate macrophage polarization and alleviate disc degenerationIntervertebral disc degeneration (IVDD) is a leading cause of chronic low back pain, contributing significantly to disability and imposing substantial economic burdens. Despite its prevalence, therapeutic strategies targeting IVDD remain limited. Recent advances in single-cell sequencing have highlighted the pivotal role of macrophages in driving the inflammatory microenvironment of degenerating intervertebral discs, particularly in the annulus fibrosus (AF). We demonstrate that macrophages infiltrating degenerated discs predominantly adopt the pro-inflammatory M1 phenotype, driving extracellular matrix degradation and AF degeneration.Specifically, we identify the glycoprotein SPP1 (osteopontin) as a key regulator of macrophage activation and M1 polarization within the disc, driving the expression of matrix metalloproteinases (MMPs) and exacerbating tissue damage. To modulate macrophage polarization and attenuate AF degeneration, we developed a novel targeted delivery system—@LEV@SPP1—by fusing siRNA-loaded liposomes with bacterial exosomes to achieve efficient macrophage targeting. However, the clinical translation of this system is challenged by the avascular nature and unique microenvironment of the intervertebral disc. To overcome these challenges, we developed a novel ROS-responsive, macrophage-targeted delivery system, AF-PTK@LEV@SPP1, by conjugating an AF-binding peptide (AF-P) to @LEV@SPP1 exosomes using a thioketal linker. This composite system leverages both macrophage specificity and ROS responsiveness to release the therapeutic payload upon elevated oxidative stress in the degenerate disc. In vivo experiments demonstrated that AF-PTK@LEV@SPP1 significantly reduced M1 macrophage polarization, alleviated AF degeneration, and promoted extracellular matrix repair, offering a promising strategy for long-term, targeted treatment of IVDD. These findings suggest that precisely modulating macrophage activity via AF-PTK@LEV@SPP1 holds substantial therapeutic potential for IVDD, with implications for regenerative strategies in other inflammatory disorders.2026/04/27GSE289741GSM8797737GSM8797736GSM8797738GSM8797733GSM8797735GSM879773425947289741Rattus norvegicus