Pulse microwave excite thermoacoustic (TA) shockwave to destroy tumor cells in situ. This has promising applications for precise tumor therapy in deep tissue. Nanoparticle (NP) with high microwave-acoustic conversion is the key to enhance the efficiency of therapy. In this study, we firstly developed defect-rich titanium nitride nanoparticles (TiN NPs) for pulse microwave excited thermoacoustic (MTA) therapy. Due to a large number of local structural defects and charge carriers, TiN NPs exhibit excellent electromagnetic absorption through the dual mechanisms of dielectric loss and resistive loss. With pulsed microwave irradiation, it efficiently converts the microwave energy into shockwave via thermocavitation effect, achieving localized mechanical damage of mitochondria in the tumor cell and yielding a precise antitumor effect. In addition to the therapeutic function, the NP-mediated TA process also generates images that provide valuable information, including tumor size, shape, and location for treatment planning and monitoring. The experimental results showed that the TiN NPs could be efficiently accumulated in the tumor via intravenous infusion. With the deep tissue penetration characteristics of microwave, the proposed TiN-mediated MTA therapy effectively and precisely cures tumors in deep tissue without any detectable side effects. The results indicated that defect-rich TiN NPs are promising candidates for tumor therapy.

Effective therapeutic strategies to precisely eradicate primary tumors with minimal side effects on normal tissue, inhibit metastases, and prevent tumor relapses, are the ultimate goals in the battle against cancer. We report a novel therapeutic strategy that combines adjuvant black phosphorus nanoparticle-based photoacoustic (PA) therapy with checkpoint-blockade immunotherapy. With the mitochondria targeting nanoparticle, PA therapy can achieve localized mechanical damage of mitochondria via PA cavitation and thus achieve precise eradication of the primary tumor. More importantly, PA therapy can generate tumor-associated antigens via the presence of the R848-containing nanoparticles as an adjuvant to promote strong antitumor immune responses. When combined with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4, the generated immunological responses will further promote the infiltrating CD8 and CD4 T-cells to increase the CD8/Foxp3 T-cell ratio to inhibit the growth of distant tumors beyond the direct impact range of the PA therapy. Furthermore, the number of memory T cells detected in the spleen is increased, and these cells inhibit tumor recurrence. This proposed strategy offers precise eradication of the primary tumor and can induce long-term tumor-specific immunity.