Amphiphilic Janus nanoparticles for nitric oxide synergistic photodynamic eradication of MRSA biofilms.

Biofilms pose significant threats to public health by causing persistent clinical infections. The development of innovative antibacterial approaches for eliminating biofilms is an urgent necessity. In this study, we developed amphiphilic Janus nanoparticles (JNPs), loaded with hydrophobic chlorin e6 (Ce6) and hydrophilic S-nitrosoglutathione (GSNO), denoted as Ce6-PDA/CaP-GSNO, with the aim to effectively eradicate biofilms and combat methicillin-resistant Staphylococcus aureus (MRSA) infections through nitric oxide (NO) synergistic photodynamic therapy (PDT). Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration ability, efficiently reaching the acidic inner layers, which triggered the rapid release of GSNO, resulting in the generation of an abundant supply of NO. NO not only exhibited potent bactericidal activity but also effectively lowered the GSH level of the biofilm, leading to enhanced efficacy of Ce6. Additionally, the interaction between NO and reactive oxygen species (ROS) resulted in the generation of reactive nitrogen species (RNS), further enhancing PDT efficacy both in vitro and in vivo. In summary, Ce6-PDA/CaP-GSNO demonstrated remarkable biofilm penetration capacity and effective reduction of the GSH level in the biofilms, leading to enhanced PDT efficacy at low photosensitizer doses and laser intensities, thereby minimizing adverse effects on normal tissues. These findings highlight the promising potential of our approach for combating biofilm-related infections.

pH/Hyal-Responsive Surface-Charge Switchable Electrostatic Complexation for Efficient Elimination of MRSA Infection.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a great threat to human health worldwide, making new effective antibacterial strategies urgently desired. In this study, a cationic pH-responsive delivery system (pHSM) was developed based on poly(ß-amino esters)-methoxy poly(ethylene glycol), by which linezolid (LZD) could be encapsulated to form pHSM/LZD. The biocompatibility and stability of pHSM/LZD were further enhanced by adding low-molecular-weight hyaluronic acid (LWT HA) on the surface through electrostatic interaction to form pHSM/LZD@HA, of which the positive surface charges were neutralized by LWT HA under physiological conditions. LWT HA can be degraded by hyaluronidase (Hyal) after arriving at the infection site. In vitro, pHSM/LZD@HA could rapidly change to being positively charged on the surface within 0.5 h under acidic conditions, especially when Hyal was present, thus promoting bacterial binding and biofilm penetration of pHSM/LZD@HA. In addition, the pH/Hyal-dependent accelerated drug release behavior was also observed and it is beneficial for the comprehensive treatment of MRSA infection in vitro and in vivo. Our study provides a novel strategy to develop a pH/Hyal-responsive drug delivery system for the treatment of MRSA infection.

Hydrogen Peroxide-Activated Nitric Oxide-Releasing Vancomycin-Loaded Electrostatic Complexation for Efficient Elimination of Methicillin-Resistant Staphylococcus aureus Abscesses.

The treatment of subcutaneous abscesses has been greatly hindered due to the spread of drug-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Thus, alternative strategies are highly desired to complement conventional antibiotic therapies and surgical intervention. As one of such strategies, applications of nitric oxide (NO) have shown great potential in the treatment of bacteria-induced subcutaneous abscesses by improving the efficacy of many therapeutic methods. However, it is extremely challenging to achieve precise delivery and controlled release because of its gaseous nature. In the present study, an effective strategy was reported in which on demand hydrogen peroxide (H2O2)-activated nitric oxide-releasing vancomycin (Van)-loaded electrostatic complexation (Lipo/Van@Arg) was fabricated. In this system, Van was encapsulated into a negative-charged DSPG/Chol liposome (Lipo/Van) and electrostatically bound with the positive-charged l-arginine (l-Arg). As expected, Lipo/Van@Arg exhibited superior bacterial binding and biofilm penetration abilities. After being in the interior of the biofilms, Lipo/Van@Arg could be triggered by the endogenous H2O2 and effectively release NO. The released NO could exhibit combined antibacterial and biofilm eradication effects with Van. Moreover, an in vivo evaluation using a BALB/c mouse model of subcutaneous abscesses indicated that the combination treatment of NO and Van based on Lipo/Van@Arg could effectively eliminate MRSA from the abscesses, thereby preventing abscess recurrence. In summary, the Lipo/Van@Arg system developed in this study realized controlled delivery and precise release of NO, which had significant clinical implications in the efficient treatment of abscesses.