Acid‐Responsive Nanobot‐Integrated Core‐Shell Microneedles Reprogram the Degenerative Annulus Fibrosus Microenvironment Through Epigenetic Suppression of Ferroptosis

Abstract

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@MgO2 metal‐phenolic nanobots that consumed pathological H+, generated O2, 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.