Excessive production of inflammatory chemokines and reactive oxygen species (ROS) can cause a feedback cycle of inflammation response that has a negative effect on cutaneous wound healing. The use of wound-dressing materials that simultaneously absorb chemokines and scavenge ROS constitutes a novel ‘weeding and uprooting’ treatment strategy for inflammatory conditions. In the present study, a composite hydrogel comprising an amine-functionalized star-shaped polyethylene glycol (starPEG) and heparin for chemokine sequestration as well as Cu
5.4
O ultrasmall nanozymes for ROS scavenging (Cu
5.4
O@Hep-PEG) was developed. The material effectively adsorbs the inflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, decreasing the migratory activity of macrophages and neutrophils. Furthermore, it scavenges the ROS in wound fluids to mitigate oxidative stress, and the sustained release of Cu
5.4
O promotes angiogenesis. In acute wounds and impaired-healing wounds (diabetic wounds), Cu
5.4
O@Hep-PEG hydrogels outperform the standard-of-care product Promogram® in terms of inflammation reduction, increased epidermis regeneration, vascularization, and wound closure.