Enhanced Piezocatalytic Therapy of Mrsa-Infected Osteomyelitis Using Ultrasound-Triggered Copper Nanocrystals-Doped Barium Titanate

Abstract

Osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) biofilms poses a major therapeutic challenge due to persistent infection and bone loss. Optimizing anti-infection and promoting bone repair are the main goals to improve the efficiency of osteomyelitis treatment. Herein, we present an ultrasound (US)-actived Cu-BTO@Gua composite piezoelectric sonosensitizer, created by conjugating guanidine (Gua) groups, a component that permeates the biofilm matrix, onto US-absorbing Cu-doped barium titanate (BTO). The guanidine groups demonstrate strong affinity for matrices abundant in negatively charged components, facilitating deeper biofilm penetration. Cu doping not only amplifies the piezoelectric effect, but also introduces abundant oxygen vacancies to suppress electron-hole pair recombination. Under US irradiation, the nanocomposite catalyzes the substrate to produce toxic ROS in the acidic infection microenvironment, while Cu depletes glutathione to aggravate oxidative stress, leading to bacterial toxin inactivation, biofilm disintegration, and bacterial death. Additionally, Cu-BTO@Gua promotes the polarization of M1 macrophages to the M2 phenotype by inhibiting nuclear factor-κB, which subsequently activates the transforming growth factor β (TGF-β) signaling pathway to support osteogenesis. This dual-action approach offers a promising strategy for improving clinical outcomes of complex bone infections.

Note:
Funding declaration: This research was supported by National Natural Science Foundation of China (Grant No. 82302720 to Y.Wu; 82125023, 82072504 to H. Xie; 82272508 to J-Y Tang; 82272562 to Z-X Wang), China Postdoctoral Science Foundation (Grant No. 2023M733964 to Y. Wu, 2023M733946 to X. Chen), Natural Science Foundation of Hunan Province (Grant No. 2023JJ40997 to Y. Wu)

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All animal-related operations in this work were approved by Center of Laboratory Animals of XiangYa Hospital Central South University (Appl. No.: XY20240508002).

Keywords: MRSA-mediated osteomyelitis, Enhanced piezoelectric effect, Biofilm disintegration, TGF-β signaling pathway, bone regeneration