Surface Charge Switchable Supramolecular Nanocarriers for Nitric Oxide Synergistic Photodynamic Eradication of Biofilms

Abstract

Biofilm has resulted in numerous obstinate clinical infections, posing severe threats to public health. It is urgent to develop original antibacterial strategies for eradicating biofilms. Herein, we develop a surface charge switchable supramolecular nanocarrier exhibiting pHresponsive penetration into an acidic biofilm for nitric oxide (NO) synergistic photodynamic eradication of the methicillin-resistant Staphylococcus aureus (MRSA) biofilm with negligible damage to healthy tissues under laser irradiation. Originally, by integrating the glutathione (GSH)-sensitive α-cyclodextrin (α-CD) conjugated nitric oxide (NO) prodrug (α-CD-NO) and chlorin e6 (Ce6) prodrug (α-CD-Ce6) into the pH-sensitive poly(ethylene glycol) (PEG) block polypeptide copolymer (PEG-(KLAKLAK) 2 -DA) via host−guest interaction, the supramolecular nanocarrier α-CD-Ce6-NO-DA was finely prepared. The supramolecular nanocarrier shows complete surface charge reversal from negative charge at physiological pH (7.4) to positive charge at acidic biofilm pH (5.5), promoting efficient penetration into the biofilm. Once infiltrated into the biofilm, the nanocarrier exhibits rapid NO release triggered by the overexpressed GSH in the biofilm, which not only produces abundant NO for killing bacteria but also reduces the biofilm GSH level to improve photodynamic therapy (PDT) efficiency. On the other hand, NO can react with reactive oxygen species (ROS) to produce reactive nitrogen species (RNS), further improving the PDT efficiency. Due to the effective penetration into the biofilm and depletion of biofilm GSH, the surface charge switchable GSH-sensitive NO nanocarrier can greatly improve the PDT efficiency at a low photosensitizer dose and laser intensity and cause negligible side effect to healthy tissues. Considering the above advantages, the strategy developed in this work may offer great possibilities to fight against biofilm infections.

A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms

“…Almost 90% microorganisms can form biofilms, in which bacterial cells are frequently embedded in a self-produced matrix of extracellular polymeric substances (EPS) which basically consist of polysaccharides, proteins, lipids and extracellular DNA [5,6]. The EPS matrix can act as a protective barrier that confers resistance to nonspecific and specific host defenses during infection and prevents the penetration of antibacterial agents [7,8]. The high resistance towards host immune response and traditional antibacterial therapy makes associated infections more intractable and challenging.…”

“…Nitric oxide (NO), as an endogenously produced molecule which plays an important role in physiological and pathophysiological processes such as wound healing and immune responses, has attracted much attention [22]. Recently, NO has been recognized as a broad-spectrum bactericidal agent which is capable of killing bacteria, especially for drug-resistant bacteria [8,15]. NO and its byproducts like nitrogen dioxide, dinitrogen trioxide and peroxynitrite can cause nitrosative and oxidative stresses on bacteria, resulting in lipid peroxidation, rupture of bacterial cell membranes, DNA cleavage and protein dysfunction [15,22].…”

Emerging nanobiomaterials against bacterial infections in postantibiotic era

“…To solve this problem, we developed a kind of synergistic bactericidal nanocarriers (α‐CD‐Ce6‐NO‐DA) that could not only show pH enhanced penetration into biofilm of photosensitizers, but also exhibit improved PDT efficacy with the assistance of nitric oxide (NO) (Figure 5). 114 …”

“…(A) Schematic diagram of the preparation process of α‐CD‐Ce6‐NO‐DA nanocarriers. (B) Schematics of the mechanisms of the MRSA biofilm‐associated infection eradication by synergistic effects between ROS (reactive oxygen species) and NO (nitric oxide) produced by α‐CD‐Ce6‐NO‐DA nanocarriers 114 …”

Recent Advances of pH‐Induced Charge‐Convertible Polymer‐Mediated Inorganic Nanoparticles for Biomedical Applications

“…Besides, it has been reported that bacterial infections and bacterial biofilms provide acidic microenvironments. [ 66 ] Therefore, these factors offer an opportunity to kill bacteria using this pH‐induced charge‐convertible strategy. Qiao et al.…”