Intracellular MRSA is extremely difficult to eradicate by traditional antibiotics, leading to infection dissemination and drug resistance. A general lack of facile and long-term strategies to effectively eliminate intracellular MRSA. In this study, glabridin (GLA)-loaded pH-responsive nanoparticles (NPs) were constructed using cinnamaldehyde (CA)-dextran conjugates as carriers. These NPs targeted infected macrophages/MRSA via dextran mediation and effectively accumulated at the MRSA infection site. The NPs were then destabilized in response to the low pH of the lysosomes, which triggered the release of CA and GLA. The released CA downregulated the expression of cytotoxic pore-forming toxins, thereby decreasing the damage of macrophage and risk of the intracellular bacterial dissemination. Meanwhile, GLA could rapidly kill intracellularly entrapped MRSA with a low possibility of developing resistance. Using a specific combination of the natural antibacterial agents CA and GLA, NPs effectively eradicated intracellular MRSA with low toxicity to normal tissues in a MRSA-induced peritonitis model. This strategy presents a potential alternative for enhancing intracellular MRSA therapy, particularly for repeated and long-term clinical applications.

Statement of significance

Intracellular MRSA infections are a growing threat to public health, and there is a general lack of a facile strategy for efficiently eliminating intracellular MRSA while reducing the ever-increasing drug resistance. In this study, pH-responsive and macrophage/MRSA-targeting nanoparticles were prepared by conjugating the phytochemical cinnamaldehyde to dextran to encapsulate the natural antibacterial agent glabridin. Using a combination of traditional Chinese medicine, the NPs significantly increased drug accumulation in MRSA and showed superior intracellular and extracellular bactericidal activity. Importantly, the NPs can inhibit potential intracellular bacteria dissemination and reduce the development of drug resistance, thus allowing for repeated treatment. Natural antibacterial agent-based drug delivery systems are an attractive alternative for facilitating the clinical treatment of intracellular MRSA infections.