Iron metabolism interference-enhanced sonodynamic therapy of methicillin-resistant Staphylococcus aureus-induced osteomyelitis by CaCO3-Ga-PPIX@PEG nanospheres

Osteomyelitis is a serious bone infection disease and is difficult to cure with antibiotic therapy. Sonodynamic therapy (SDT) is an alternative treatment option for deep-seated infections by killing bacteria through reactive oxygen species (ROS). However, the bacterial antioxidant system suppresses the therapeutic efficacy of SDT. Herein, CaCO3-Ga-PPIX@PEG nanospheres (CaGaPP NSs) were prepared to inhibit the bacterial antioxidant system and enhance the SDT therapeutic efficacy for treating methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis in the rat. In the acidic infection microenvironment, gallium ion (Ga3+) and protoporphyrin (PPIX) can be released from CaGaPP NSs. Ga3+ can act as a "Trojan horse" of Fe3+ to inactivate bacteria by interfering with their iron metabolism. Moreover, CaGaPP NSs have sonodynamic activity and produce 1O2 and O2·- under ultrasound (US) irradiation. Ga3+ can inhibit the activity of bacterial superoxide dismutase (SOD) and further increase the sensitivity of bacteria to O2·-, thereby enhancing the antibacterial activity of SDT. CaGaPP NSs combined with US irradiation can kill 99.97% MRSA in rats with osteomyelitis and effectively promote the tissue healing of the infected bone. This study demonstrates a multifunctional gallium-based sonosensitizer with iron metabolism interference and oxidative stress-sensitizing properties, which provides a promising SDT therapeutic agent for effective treatment of osteomyelitis.