An H₂O₂/Acidic Microenvironment-Responsive Theranostic Nanoplatform Promotes Spinal Cord Injury Repair via MRI-Guided Synergistic Anti-Ferroptosis.

Abstract

The secondary injury cascade following spinal cord injury (SCI) involves complex pathological processes, with the interplay between ferroptosis and oxidative stress serving as a key impediment to neural repair. Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis, faces limitations in clinical translation due to its low delivery efficiency and poor targeting in vivo. To address this, we constructed a theranostic nanoplatform based on mesoporous polydopamine (M-PDA), designated M-PDA@MnO₂@Fer-1, aiming to achieve targeted drug delivery and visual monitoring of the treatment process. The MnO₂ shell of this platform undergoes responsive degradation in the acidic and hydrogen peroxide (H₂O₂)-enriched microenvironment of the injured site. This process not only triggers the controlled release of Fer-1 but also generates Mn²⁺ ions that act as a T₁-weighted magnetic resonance imaging (MRI) contrast agent, enabling real-time tracking of drug accumulation at the lesion. In vitro and in vivo experiments demonstrated that this system effectively targets the SCI region, significantly suppresses lipid peroxidation and ferroptosis-associated signaling pathways, and promotes the repair of axonal and myelin structures. Behavioral assessments and imaging analyses further confirmed that rats treated with M-PDA@MnO₂@Fer-1 exhibited the most significant recovery of motor function. This study provides an intelligent nano‑therapeutic strategy for SCI that integrates microenvironmental responsiveness, targeted treatment, and real‑time imaging surveillance. STATEMENT OF SIGNIFICANCE: An integrated nanoplatform (M-PDA@MnO₂@Fer-1) is developed for spinal cord injury (SCI). The MnO₂ shell degrades in the acidic/H₂O₂-rich SCI microenvironment, triggering Fer-1 release and generating Mn²⁺ for T₁-weighted MRI. This design uses the same MnO₂ component for both drug release and imaging. MnO₂ consumption of H₂O₂ provides antioxidant effects that complement Fer-1-induced ferroptosis inhibition. MRI signal changes correlate with nanoplatform accumulation at the injury site, enabling non-invasive estimation of local drug concentration. This work offers an integrated strategy for MRI-guided, microenvironment-responsive anti-ferroptosis therapy in SCI.