Platelet-Derived Growth Factor Receptor α-Targeted Cell Membrane-Camouflaged Nanotherapy Disrupts Fibrosis-Inflammation Coupling in Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IVDD) is a primary cause of chronic low back pain. Although inflammation is a prominent feature of degenerating discs, anti-inflammatory therapies often provide limited and transient benefit, suggesting that disc degeneration is maintained by a more stable tissue-level program. We therefore hypothesized that IVDD is sustained by a fibrosis-inflammation-coupled cell state, and that effective intervention requires both disrupting fibrotic signaling and overcoming the delivery barriers imposed by the disc's avascular, ECM-dense environment. To test this, we integrated clinical stratification, single-cell transcriptomics, and mechanical modeling to identify pathogenic nucleus pulposus (NP) cell states. Single-cell mapping revealed an expanded fibrosis-inflammation-coupled NP subpopulation in degenerated discs, characterized by the concurrent activation of ECM remodeling and inflammatory programs. Mechanical stress locked NP cells in this state, inducing persistent inflammation even after stimulus removal, suggesting that fibrosis is an upstream driver. We developed a platelet-derived growth factor receptor α (PDGFRα)-targeted NP membrane vesicle (NMV)-coated nanotherapeutic (NMV@PC) with a dual antifibrotic drug system. This therapy effectively suppressed profibrotic pathways, targeted fibrotic NP cells, and restored disc height and hydration in a lumbar spine instability model. NMV@PC reduced collagen deposition, inflammatory mediators, and pain-related behaviors, reprogramming degenerated discs toward a homeostatic state and overcoming structural delivery barriers.