Dual-Functional Hydrogel Platform Suppresses M1 Activation and Stabilizes M2 Macrophages in Intervertebral Disc Degeneration

Immune infiltration is a key factor of inflammatory responses and tissue remodeling during tissue injury and degeneration. In the immune microenvironment of degenerated intervertebral discs, the dynamic balance between M1 and M2 macrophage polarization is disrupted, impairing both frontline anti-inflammatory defense and rear tissue repair. Conventional single-target strategies are limited in their ability to simultaneously suppress inflammatory amplification and stabilize reparative capacity--often resulting in a “frontline unsettled, rear compromised” scenario. Here, we developed an “offense-defense synergy” macrophage reprogramming hydrogel platform that integrates dual physical-chemical regulatory mechanisms to achieve synergistic intervention at both the offensive and defensive ends. The platform incorporates reactive oxygen species (ROS)-responsive dynamic covalent bond-based phenylboronic ester-functionalized nanoparticles, enabling precise scavenging of excessive ROS during the inflammatory phase, thereby blocking the M1-driven inflammatory amplification loop and rapidly attenuating frontline inflammatory signaling. Concurrently, an embedded poly-L-lactic acid (PLLA) scaffold delivers localized electrical stimulation during the reparative phase to prevent rear M2 repolarization and promote extracellular matrix (ECM) regeneration, achieving full-cycle precision control over macrophage fate. Experimental results in a rat puncture-induced intervertebral disc degeneration model showed that this strategy enhanced disc repair outcomes, indicating its potential for multifaceted therapeutic intervention. This “offense-defense synergy” immunoregulatory approach provides a potential material-based strategy for intervertebral disc degeneration (IVDD) and may inform the design of precision immunomodulation platforms.