| Summary: | Infected diabetic wound (DW) healing entails a series of temporally and spatially regulated stages including antibacterial responses, revascularization, and collagen deposition, underscoring the need for the controlled sequential delivery of appropriate compounds when treating these wounds. Here, we designed a multifunctional core–shell CTS@PLCL/DWJM@Cu nanofiber loaded with three bioactive agents, including chitosan (CTS), copper (Cu), and decellularized Wharton’s jelly matrix (DWJM). We used this platform to facilitate regulated antibacterial, angiogenic, and collagen deposition activity in the context of DW healing. These CTS@PLCL/DWJM@Cu nanofibers exhibited satisfactory mechanical properties, excellent absorption, acceptable biodegradability, a high level of biocompatibility, elevated adhesive rates, and the ability to sequentially mediate controlled sequential CTS and Cu release. Further in vitro analyses revealed that the initial release of the CTS shell was sufficient to exert antibacterial activity, after which the sustained release of the Cu core promoted cellular migration, neovascularization, and enhanced angiogenesis-related gene expression. In vivo, DWJM further accelerated the deposition of collagen. Together, the sequential antibacterial, angiogenic, and collagen deposition activities synergistically enhanced DW healing. We thus posit that the core–shell CTS@PLCL/DWJM@Cu nanofiber holds great promise for use as a dressing material capable of promoting the appropriate stages of DW healing in a regulated, sequential manner.
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