Micro-nano therapeutic platform combats disc degeneration: ChsMA microspheres with ROS-scavenging metal-phenolic armor and puerarin nanocargo for triple-targeted ECM regeneration

• Designed a hierarchical micro-nano platform integrating ECM-mimetic microspheres and MPNs. • Introduced a strontium-tannic acid metal-phenolic “armor” for broad-spectrum ROS scavenging. • Enabled sustained release of puerarin nanoparticles for prolonged anti-inflammatory action. • Achieved triple-targeted therapy to disrupt ROS/inflammation/ECM degradation feedback loop. • Demonstrated minimally invasive, injectable treatment enabling disc regeneration and pain relief in vivo. To disrupt the pathogenic cycle of inflammation and oxidative stress driving intervertebral disc degeneration (IDD), we engineered a hierarchical micro-nano therapeutic platform (CPM). This system integrates Chondroitin sulfate methacrylate (ChsMA) hydrogel microspheres mimicking the extracellular matrix (ECM), Pluronic F-127 nanoparticles encapsulating anti-inflammatory puerarin for sustained release (52.6 % over 28 days), and a metal-phenolic network (MPN) “armor” of tannic acid (TA) and strontium ions (Sr 2+ ) providing broad-spectrum reactive oxygen species (ROS) scavenging (>83 % clearance) and enzyme-mimetic activity. CPM synergistically neutralizes oxidative stress, suppresses inflammation, and protects ECM integrity. In vitro, CPM demonstrates excellent biocompatibility and multi-target efficacy, concurrently suppressing inflammation, scavenging ROS, restoring mitochondrial function, and promoting ECM regeneration in stressed nucleus pulposus cells. In a rat IDD model, a single minimally invasive injection of CPM provides sustained drug retention (38.1 % at 2 weeks), preserves disc structure and proteoglycan content, and restores T2-MRI signals. This triple-synergistic strategy represents a promising therapeutic paradigm for arresting IDD progression.