Multifunctional cascade theranostic agents for synergistic photothermal/ferroptosis/immuno antitumor therapy

Photothermal therapy (PTT) has achieved tremendous advances against various cancers. However, it encounters uneven heat distribution caused by the limited penetration of the excitation light. Besides, the intrinsic heat resistance mechanisms in the tumor microenvironment limit antitumor efficacy and impose the potential risks of metastasis. To solve the suboptimal therapeutic effect of PTT, we have engineered photothermal agents with high photothermal conversion efficiency (PCE) in NIR-II, combined with ferroptosis therapy, to achieve an efficient tumor inhibition effect. Specifically, we develop porous Bi₂Te₃ with high and stable PCE (68.35 %) at NIR-II (1060 nm) for PTT. The decoration of Fe₃O₄ nanoparticles on the porous Bi₂Te₃ increased PCE to 79.25 %, which induced ferroptosis. As a result, the intracellular Fe^3 +-mediated Fenton reaction process is accelerated by PTT-induced local hyperthermia, and ferroptosis increases the thermal sensitivity of the tumor cells, resulting in an excellent therapeutic effect. In addition, the tumor-associated antigen released after the synergy of PTT/ferroptosis can also cause immunogenic cell death (ICD) due to the exposure of CRT and HMGB1, which are the "eat me" signals. Notably, Bi₂Te₃ and its synthesis template lanthanide-doped nanoparticles (LnNPs) are excellent candidates for X-ray, photoacoustic, and optical imaging (Er³⁺-activated 1525 nm downshifting luminescence ). They enable real-time imaging in deep tissue penetration with a high temporal and spatial resolution to guide precise antitumor treatment in situ. Furthermore, the resultant LnNP@Bi₂Te₃-Fe₃O₄ nanocomposites (LBT-Fe) can achieve X-ray/photoacoustic/NIR-II imaging-guided synergistic ferroptosis/PTT/immuno tumor therapy.