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.