On-Demand Multifunctional Electrostatic Complexation for Synergistic Eradication of MRSA Biofilms

Recently, methicillin-resistant Staphylococcus aureus (MRSA) severely threatened the public health, especially when the biofilms developed. Although the biofilm eradication capability of nanoparticles (NPs) has been proposed and confirmed, efficient biofilm penetration and retention are still a big challenge. To solve this problem, a multifunctional electrostatic complexation (denoted as TDZ-G4@CA) was constructed for biofilm combination therapy. TDZ-G4@CA was composed of a TDZ-grafted amino-ended poly(amidoamine) dendrimer (TDZ-PAMAM) as the inner core and cis-aconitic anhydride-modified d-tyrosine (CA-Tyr) wrapped outside via electrostatic interaction. In our design, TDZ-G4@CA could simultaneously reduce the particle size and reverse the surface charge under an acidic microenvironment, which was designed for efficient biofilm penetration and retention. Meanwhile, the on-demand two-step sequential delivery of biofilm dispersal and antibacterial agents was also obtained. The acid responsiveness of TDZ-G4@CA triggered the immediate release of d-Tyr to damage the matrix of the biofilm. Subsequently, TDZ-G4 could penetrate over the depth of the biofilm and bind tightly to MRSA, which could enhance the permeability of the bacterial membrane for TDZ internalization. Additionally, TDZ exhibited a sustained-release pattern as a response to lipase to maintain an effective bactericidal concentration for a long time. As expected, in vitro experiments demonstrated that surface charge/particle size-adaptive TDZ-G4@CA with a sequential delivery strategy exhibited intensive infiltration in the biofilm matrix and excellent biofilm eradication capabilities. Afterward, in vivo experimental results also confirmed the prolonged circulation time and comprehensive therapeutic efficacy of TDZ-G4@CA against MRSA-induced subcutaneous abscess without any systemic side effects. Based on the comprehensive evaluation of the therapeutic outcome, the electrostatic complexation (TDZ-G4@CA) can serve as a promising strategy for enhanced antibiotic therapy for combating biofilm-associated infections.