Dysregulation of growth factor expression causes impaired healing of diabetic foot ulcer (DFU). Platelet-derived growth factor (PDGF)-containing gel has been clinically applied for topical treatment of DFU. Recruitment of neutrophils stimulated by PDGF favors the wound healing of DFU. However, overactivation of neutrophils induced by hyperglycemia causes massive generation and long-term persistence of neutrophil extracellular traps (NETs), ultimately leading to unexpected skin damage and delayed wound repair. Here, we engineer a hierarchically-assembled hydrogel to achieve local release of the growth factor, PDGF-BB and the NET scavenger, deoxyribonuclease (DNase) I with distinct kinetics for enhanced healing of DFU. The hydrogel is constructed by crosslinking of anti-bacterial quaternized chitosan and hypochlorite-degradable nanogel via a copper-free click reaction, in which PDGF-BB is loaded in the hydrogel matrix while DNase I is encapsulated in the inner nanogel. Programmable release of combinatorial therapeutics is implemented by the hydrogel in response to the wound microenvironment. We show that the hierarchical hydrogel co-loaded with PDGF-BB and DNase I promotes neutrophil recruitment, increases endothelial cell migration, degrades excess NETs, and prevents wound infection for accelerating the wound closure in the diabetic mouse wound models.
