Engineering oxygen-deficient ZrO2-x nanoplatform as therapy-activated “immunogenic cell death (ICD)” inducer to synergize photothermal-augmented sonodynamic tumor elimination in NIR-II biological window

Nano-zirconia, as an amphoteric semiconductor, has been industrially exploited in photocatalytic reactions and as piezoelectric sensors. However, its biomedical applications, especially in antitumor therapeutics, have been seldom investigated to date. Here, oxygen-deficient zirconia (ZrO2-x)-based nanoplatform with surface PEGylation and cyclic-Arg-Gly-Asp (cRGD) peptide functionalization (ZrO2-x@PEG/cRGD, abbreviated as ZPR) was rationally designed and established for the first time, which was utilized as therapy-activated “immunogenic cell death (ICD)” inducer to boost photothermal-augmented sonodynamic tumor elimination in NIR-II biological window. As-synthesized ZPR nanoparticles (NPs) exhibited intense optical absorbance in the wavelength range of 900–1100 nm, which endowed ZPR NPs with a photothermal conversion efficiency as high as 45.8% for photothermal therapy (PTT). Moreover, owing to the abundant surface oxygen defects, ZPR NPs can serve as a category of high-performance nano-sonosensitizer based on the strengthened separation of electron (e−)/hole (h+) pairs from the energy band under external ultrasound (US) activation. More importantly, cytotoxic reactive oxygen species (ROS) generated from sonodynamic therapy (SDT) can effectively induce immunogenic cell death (ICD), which is regarded to be significant to boost systemic anti-tumor immunity for rendering a complete tumor eradication post-treatment. In vivo experiments on tumor xenografts demonstrated the high therapeutic efficacy upon photothermal-augmented sonodynamic therapy, with the aid of photoacoustic (PA) imaging navigation. Remarkably, the level of inflammatory cytokines, including type I interferon (IFN), tumor necrosis factor α (TNF-α) as well as interleukin (IL-6) were systemically upgraded after NIR-II/US irradiation, verifying the promotion of immunogenicity. Taken together, this study delivers useful insights for extending the applications of zirconia as promising translational medicine for tumor theranostics in the near future.