Photodynamic/photothermal pH-responsive mannose-based dimeric prodrug for synergistic overcoming the biological barriers to conquer multidrug resistance in MRSA

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA), recognized for its resistance, poses a formidable challenge to public health, primarily attributable to its biochemical resistant mechanisms, capacity to form protective biofilms, and capacity to evade macrophage surveillance. In response to this threat, we constructed a multifunctional pH-responsive dimeric prodrug based on mannose (MAN) and cinnamaldehyde (CMA). This prodrug, designated as MACA@indocyanine green (ICG), incorporates the photosensitizer ICG. The nanoscale properties and MAN units integrated into the MACA@ICG prodrug could promote effective binding with infectious microbes or MAN residues on mammalian cells. This specific interaction, corroborated by co-localization studies using confocal microscopy and flow cytometry, is crucial for initial bacterial binding, biofilm penetration, and macrophage-specific uptake, all of which are strategic in surmounting the biological barriers posed by MRSA. Following its targeted accumulation, MACA@ICG was demonstrated responsiveness to the acidic microenvironment of bacteria to release free CMA, a natural compound with antimicrobial properties. The drug release, synergistically coupled with the effects of photothermal therapy (PTT) and photodynamic therapy (PDT) showcased superior synergistic antibacterial efficacy both in vitro and in vivo. Therefore, MACA@ICG was verified remarkable capabilities in surmounting bacterial biological barriers and exceptional antibacterial efficiency through the combinational treatments of herbal components, PDT and PTT.