酸响应纳米机器人集成核壳微针，通过表观遗传抑制铁死亡重塑退变纤维环微环境

Abstract

Annulus fibrosus (AF) rupture is a key structural event in intervertebral disc degeneration, but effective repair is hindered by the acidic, hypoxic and oxidative microenvironment of the avascular disc. Single‐cell transcriptomic reanalysis and clinical AF specimens identified ferroptosis‐associated redox imbalance as a prominent feature of advanced degeneration. Here, we developed an acid‐responsive nanobot‐integrated core‐shell microneedle system for staged annulus fibrosus repair. The shell layer released TA@MgO 2 metal‐phenolic nanobots that consumed pathological H + , generated O 2 , and provided NIR‐amplified redox buffering, thereby normalizing the early degenerative microenvironment. The core layer enabled sustained quercetin release to reinforce anti‐ferroptotic and matrix‐preserving effects. Mechanistically, TMH/QG+NIR suppressed ferroptosis in AF cells by epigenetically silencing ATF3 through DNMT3A‐dependent promoter methylation, thereby relieving ATF3‐mediated repression of SLC7A11 and restoring GPX4‐dependent antioxidant defense. In a puncture‐induced degeneration model, this system alleviated ferroptotic injury, improved AF integrity, preserved disc height and enhanced biomechanical resilience. These findings identify the DNMT3A‐ATF3‐SLC7A11 axis as a therapeutically tractable ferroptosis‐regulatory pathway and establish a staged microenvironment‐reprogramming strategy for AF repair. An acid‐responsive core‐shell microneedle system normalizes the degenerative annulus fibrosus microenvironment by consuming pathological H + , generating O 2 , and providing NIR‐amplified redox buffering. Mechanistically, it epigenetically suppresses ferroptosis via DNMT3A‐dependent methylation of the ATF3 promoter, relieving ATF3‐mediated repression of SLC7A11 and restoring GPX4‐mediated antioxidant defense, thereby establishing a staged repair strategy for annulus fibrosus regeneration.