Photodynamic Cationic Ultrasmall Copper Oxide Nanoparticles-Loaded Liposomes for Alleviation of MRSA Biofilms

Xiangjun Chen,* Wenting Li,* Xueling Li, Keke Li, Guilong Zhang, Wei Hong School of Pharmacy, Shandong New Drug Loading & Release Technology and Preparation Engineering Laboratory, Binzhou Medical University, Yantai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Hong; Guilong Zhang, Tel/Fax +86-0535-6908191 ; Tel/Fax +86-0535- 6913719, Email hongwei_sy@bzmc.edu.cn; glzhang@bzmc.edu.cnIntroduction: As we enter the post-antibiotic era, the rise of antibiotic-resistant pathogenic bacteria is becoming a serious threat to public health. This problem is further complicated by antibiotic-resistant biofilms, for which current treatment options are limited.Methods: To tackle this challenge, we propose a novel approach that involves the use of photodynamic cationic pH-sensitive liposomes loaded with ultra-small copper oxide (Ce6@Lipo/UCONs) to effectively eliminate drug-resistant bacteria and eradicate biofilms while minimizing safety concerns and the risk of resistance development.Results: Our study demonstrates that Ce6@Lipo/UCONs have minimal toxicity to mammalian cells and can significantly enhance the association affinity with methicillin-resistant Staphylococcus aureus (MRSA) as confirmed by fluorescent microscope and flow cytometry, thereby greatly improving the bactericidal effect against planktonic MRSA. The cationic nature of Ce6@Lipo/UCONs also enables them to penetrate MRSA biofilms and respond to the acidic microenvironment within the biofilm, effectively releasing the loaded UCONs. Our results indicate that Ce6@Lipo/UCONs could effectively eliminate biofilms under light irradiation conditions, as evidenced by both biomass analysis and scanning electron microscopy observations. In addition, significant antibacterial effects and abscess healing were observed in MRSA-infected mice treated with Ce6@Lipo/UCONs upon light irradiation, while good biocompatibility was achieved in vivo.Conclusion: Taken together, our findings suggest that photodynamic cationic ultrasmall copper oxide nanoparticles-loaded liposomes are a highly promising nano platform for combating antibiotic-resistant microbial pathogens and biofilms. The effective biofilm penetration and synergistic effect between photodynamic inactivation and metal sterilization make them a valuable tool for overcoming the challenges posed by antibiotic resistance.Keywords: biofilm, antibiotic resistance, synergistic potential, photodynamic inactivation, metal sterilization