Liquid exfoliation of TiN nanodots as novel sonosensitizers for photothermal-enhanced sonodynamic therapy against cancer

Ultrasound (US)-activated sonodynamic therapy (SDT), as a non-invasive therapy method, has the advantages of large tissue penetration depth promising for treatment of large internal tumors. However, due to the hypoxic characteristic of tumor microenvironment and lack of effective sonosensitizers, the efficacy of SDT is still not satisfactory. In addition, there is still a lot of space for the exploration of SDT-based collaborative cancer treatment. Herein, ultra-small titanium nitride (TiN) nanodots are successfully synthesized for photothermal-enhanced SDT against cancer. Ultra-small TiN nanodots with an average size of 1.5 nm are prepared by the liquid exfoliation method. The obtained TiN nanodots have satisfactory second near-infrared (NIR II) absorption, which can be used for photoacoustic (PA) imaging and photothermal therapy (PTT) of tumors. Interestingly, TiN nanodots can also be used as efficient sonosensitizers to generate reactive oxygen species (ROS) under US irradiation owing to the special defect structure and surface partial oxidation to TiO2 for sonodynamic cancer therapy. The mild photothermal heating of tumors generated by TiN nanodots under NIR II laser irradiation can facilitate intra-tumoral blood flow and improve tumor oxygenation, thereby achieving a significant synergistic treatment effect by combining PTT and SDT. Importantly, most of these TiN nanodots due to their ultra-small size can be promptly metabolized from the mouse body, thus avoiding the concerns about long-term toxicity of nanomaterials. Our work thus for the first time demonstrates the potential use of metal nitride nanomaterials as a new type of multifunctional nano-agents with intriguing properties for cancer theranostic applications.