An injectable ROS-scavenging hydrogel with engineered Rehmannia glutinosa extracellular vesicles designed for inflammation-resolving tissue regeneration

This study prepared a functional composite hydrogel based on gelatin and hyaluronic acid with ROS responsiveness and loaded with C-REVs, which has an efficient drug delivery function to improve intervertebral disc degeneration and promote tissue repair. • A new type of functional hydrogel was prepared, which has good ROS response and clearance ability in inflammatory sites. • The extracted extracellular vesicles of R. glutinosa have suitable particle size, abundant bioactive substances, and excellent anti-inflammatory effects. • This synergistic interaction strategy proved that the functional hydrogel loaded with C-REVs have a dual gradient therapy. The regulation of inflammation is critical for effective tissue regeneration and repair. Since excessive reactive oxygen species (ROS) and pro-inflammatory factors are key pathological hallmarks of inflammation, their suppression is essential for mitigating inflammatory responses. Herein, we developed a ROS-responsive hydrogel incorporating catalpol-engineered Rehmannia glutinosa extracellular vesicles (C-REVs) to scavenge ROS, precisely inhibit inflammatory mediators, and thereby promote the repair of damaged skin and intervertebral disc tissues. The fabricated hydrogel exhibited excellent ROS-scavenging capacity, injectability, and biocompatibility, indicating its suitability for minimally invasive administration. In vitro experiments demonstrated that the ROS-responsive hydrogel effectively eliminated excess intracellular ROS and significantly suppressed cellular inflammatory responses under oxidative stress conditions. Moreover, in vivo results revealed that C-REVs released from the hydrogel promoted macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, further alleviating local inflammation and creating a favorable microenvironment for tissue regeneration. The synergistic action between the ROS-responsive hydrogel and engineered C-REVs enabled sustained attenuation of inflammation and regulated immune responses, and facilitated the repair and regeneration of injured tissues. This composite system represents a promising and efficacious therapeutic strategy for treating intervertebral disc degeneration and skin injuries.