Protoporphyrin-sensitized degradable bismuth nanoformulations for enhanced sonodynamic oncotherapy

Decreasing the scavenging capacity of reactive oxygen species (ROS) and enhancing ROS production are the two principal objectives in the development of novel sonosensitizers for sonodynamic therapy (SDT). Herein, we designed a protoporphyrin-sensitized bismuth-based semiconductor (P-NBOF) as a sonosensitizer to generate ROS and synergistically depleted glutathione for enhanced SDT against tumors. The bismuth-based nanomaterial (NBOF) is a wide-bandgap semiconductor. Sensitization by protoporphyrin made it easier to excite electrons under ultrasonic stimulation, and the energy of the lowest unoccupied electron orbital in protoporphyrin was higher than the conduction-band energy of NBOF. Under ultrasound excitation, the excited electrons in the protoporphyrin were injected into the conduction band of the NBOF, increasing its reducing ability leading to the production of more superoxide anion radicals and also helping to increase the charge separation of protoporphyrin leading to the production of more singlet oxygen. Meanwhile, P-NBOF continuously depleted glutathione, which was not only conducive to breaking the redox balance of the tumor microenvironment to enhance the therapeutic efficacy of SDT, but also promoted its degradation and metabolism. The construction of this P-NBOF sonosensitizer thus provided an effective strategy to enhance SDT for tumors. STATEMENT OF SIGNIFICANCE: To enhance the efficacy of sonodynamic tumor therapy, we developed a degradable protoporphyrin-sensitized bismuth-based nano-semiconductor (P-NBOF) by optimizing the band structure and glutathione-depletion ability. Protoporphyrin in P-NBOF under excitation preferentially generates free electrons, which are then injected into the conduction band of NBOF, improving the reducing ability of NBOF and promoting the separation of electron-hole pairs, thereby enhancing the production capacity of reactive oxygen species. Furthermore, P-NBOF can deplete glutathione, reduce the scavenging of reactive oxygen species, and reactivate and amplify the effect of sonodynamic therapy. The construction of the nanotherapeutic platform provides an option for enhancing sonodynamic therapy.