Hybrid membrane nanovesicles reprogram macrophages to resolve oxidative stress in intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is sustained by a self-amplifying inflammatory microenvironment in which oxidative stress and macrophage activation form a pathogenic feedback loop that drives matrix disorganization and progressive tissue failure. However, therapeutic disruption of this immune-redox circuit remains challenging because drugs poorly access the avascular disc niche and rarely modulate both immune and structural compartments simultaneously. Here we develop a hybrid membrane-engineered nanovesicle system (DP@HMV) derived from macrophage and nucleus pulposus cell membranes to enable dual-compartment targeting within degenerative discs. This platform delivers daphnetin and pioglitazone in a co-assembled nanocore and permits intervention at the level of the pathological microenvironment rather than single signaling pathways. Mechanistically, DP@HMV quenches excessive reactive oxygen species and interrupts pro-inflammatory amplification by reprogramming macrophages toward a reparative phenotype. This immune shift is coupled to restoration of matrix homeostasis, characterized by enhanced anabolic matrix synthesis and suppression of fibrotic and catabolic remodeling. Transcriptomic analyses further reveal coordinated downregulation of inflammatory and matrix-degrading programs, indicating systemic rewiring of the degenerative niche. In a rat model of IVDD, DP@HMV preserves disc structure, improves histological integrity, and alleviates pain-associated behaviors. These findings demonstrate that hybrid membrane nanotherapy can reprogram the macrophage-driven redox microenvironment, establishing a microenvironment-centered strategy for treating IVDD.