Currently, treatment of chronically infected wounds still remains a big challenge; thus, a novel strategy with a highly efficient therapeutic effect is of urgent demand. In the present work, we demonstrated that combinational use of nitric oxide (NO) and deferoxamine (DFO) is a promising way for treating hard-to-heal wounds. As a proof of concept, DFO was first loaded in mesoporous polydopamine (mPDA) and then functionalized by a chitosan-graft-third generation poly(amidoamine) polymer with terminal S-nitrosothiol groups (CP-SNO) via a strong electrostatic interaction, obtaining a multifunctional nanocomposite mPDA@DFO@CP-SNO. Upon near-infrared laser irradiation, mPDA@DFO@CP-SNO displayed a mild-temperature photothermal effect (MPTT) and a simultaneous NO and DFO controlled release property. The synergistic MPTT and NO antibacterial effect of mPDA@DFO@CP-SNO enabled effective elimination of both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus (S. aureus), as well as the biofilms formed by both bacteria. An in-depth mechanistic study revealed that mPDA@DFO@CP-SNO possessed particular binding affinity to the bacterial membrane, which significantly enhanced the damage effect on the bacterial membrane followed by boosting intracellular reactive oxygen species generation to accelerate GSH depletion and DNA dysfunction, finally leading to bacterial death. Moreover, the anti-inflammation and wound-healing effectiveness of mPDA@DFO@CP-SNO were demonstrated on an in vitro cell scratch model and an in vivo S. aureus-infected rat full-thickness skin wound model. Thanks to the triple therapeutic effects of MPTT, DFO, and NO, mPDA@DFO@CP-SNO significantly relieved the inflammation in rats’ infected wounds and promoted wound skin regeneration by upregulating expression of the hypoxia-inducible factor (HIF)-1α and the vascular endothelial growth factor.

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