A hypoxia-irrelevant Fe-doped multivalent manganese oxide sonosensitizer via a vacancy engineering strategy for enhanced sonodynamic therapy

Sonodynamic therapy (SDT), as a noninvasive treatment with preferable therapeutic depth, has attracted widespread attention. However, current sonosensitizers suffer from a low quantum yield of ultrasound (US)-triggered reactive oxygen species (ROS), and their efficacy is greatly compromised by hypoxia, a characteristic feature of most solid tumors. To address this issue, a hypoxia-irrelevant sonosensitizer, namely, Fe-doped multivalent manganese oxide nanoparticle (FDMN), was developed via an oxygen vacancy engineering strategy. The prepared FDMNs possessed sufficient oxygen vacancies (OVs) due to the doping of Fe3+ into the multivalent manganese oxide lattice, which allowed efficacious ROS generation by preventing the recombination of sono-triggered electron-hole pairs. Specifically, due to the OVs structures, oxygen molecules were adsorbed on the surface of FDMNs, bestowing nanosonosensitizers with a hypoxia-irrelevant singlet oxygen (1O2) generation ability, which has not been shown before. Furthermore, FDMNs were capable of catalyzing endogenous O2 into highly toxic 1O2 without any exogenous stimulus to realize ROS overproduction, inherited from multivalent manganese oxides, and eliminating glutathione (GSH) to amplify the oxidative stress. All these synergistic effects result in a superior therapeutic outcome even in hypoxic microenvironment. Overall, this work illustrates that the vacancy engineering strategy is a favorable method to rationally construct a hypoxia-irrelevant sonosensitizer for highly efficient and safe SDT.