Xiaolin Pan, Yanwen Ding, Hao Han, Songfeng Chen, Hongjian Liu, Haifeng Zhou, Chengwei Li, Zhe Yang, Guiying Li, Lin Jin
Responsive hydrogels hold significant promises for precision biomaterial-based therapies and controlled drug delivery. However, persistent inflammatory mediators, the degenerative inflammatory microenvironment, and intrinsic immune responses to implanted scaffolds continue to impede their clinical translation. Here, we developed a reactive oxygen species (ROS)-responsive hydrogel (PVA-CS@HA) that functions as a smart delivery platform for quercetin-loaded kiwifruit extracellular vesicles (KEVs-Q). The hydrogel is cross-linked through a ROS-cleavable linker and selectively degrades within inflammatory microenvironments, simultaneously scavenging excessive ROS and enabling spatiotemporal release of KEVs-Q to regulate gene expression and restore immune homeostasis. This dual functionality couples the intrinsic immunomodulatory activity of plant-derived vesicles with the antioxidant and anti-inflammatory properties of quercetin, yielding synergistic therapeutic outcomes. Furthermore, the composite hydrogel exhibits excellent injectability, strong tissue adhesion, and tunable degradation kinetics, ensuring responsive delivery at pathological sites. Transcriptomic analysis identifies antioxidant gene activation, inflammatory suppression, NF-κB, TNF, and PI3K-Akt pathway modulation underlying its bioactivity. The hydrogel mitigated inflammation-driven fibroblast activation and enhanced tissue repair across multiple models. Through ROS-responsive scaffolding and loaded vesicle integration, it establishes an adaptive platform for dynamic immunomodulation. The PVA-CS@HKEVs-Q platform highlights a broadly applicable and clinically translatable strategy for inflammation-associated tissue repair, advancing next-generation regenerative therapies.