Mild-Temperature Photothermal Effect Triggers Simultaneous Nitric Oxide- and Deferoxamine-Releasing Mesoporous Polydopamine-Based Nanoplatform for Robust Antibacterial, Anti-inflammation, and Wound-Healing Activity

Abstract

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.

Revealing the antibacterial power of hydrogen-releasing PdH nanohydride against drug resistant Staphylococcus aureus: an in-depth mechanism study

“…Up to now, nitric oxide (NO), carbon monoxide (CO), hydrogen sulfide (H 2 S) and sulfur dioxide (SO 2 ) have been explored and proved to be active in killing various types of bacteria, including MDR bacterial strains. [7][8][9][10] Nevertheless, high use of the above-mentioned gases can also trigger adverse side effects and cause lots of pain or even death in patients, which has largely impeded their potential translation to clinics. Hydrogen (H 2 ) is the smallest gas with a high reducing ability, and it is now being widely explored in treating many types of diseases like Alzheimer's, Parkinson's, cancer, etc.…”

Multifunctional antibiotics-free hydrogel dressings with self-regulated nitric oxide-releasing kinetics for improving open wound healing

“…On the one hand, NO is considered to be a broadspectrum antibacterial agent, and there is currently no evidence to support that NO induces the production of drug-resistant bacteria. [8][9][10] NO is intrinsically unstable in a biological environment, and rapidly reacts with superoxide to produce peroxynitrite (ONOO À ) and nitrous trioxide (N 2 O 3 ) and other products. These products can induce lipid peroxidation to disrupt bacterial membranes, eventually leading to DNA deamination and oxidative damage to cause bacterial necrosis.…”

Near-Infrared-Induced NO-Releasing Photothermal Adhesive Hydrogel with Enhanced Antibacterial Properties

“…15,21 Nevertheless, NO has various drawbacks, like being hard to control and very low efficiency in targeted delivery, which in turn hinder its broad use. 1 To achieve satisfactory therapeutic outcomes, more effort should be given to efficient loading and release of NO in a controlled manner. Till now, various NO donors such as Snitrosothiols (SNO), diazeniumdiolates (NONOates), Nnitroso amines, etc.…”