Transformable Nanosensitizer with Tumor Microenvironment-Activated Sonodynamic Process and Calcium Release for Enhanced Cancer Immunotherapy

Despite the promise of sonodynamic processes in cancer therapy, existing sonosensitizers often fail to regulate the generation of reactive oxygen species (ROS) against tumors, potentially leading to off-target toxicity to normal tissues. We report a transformable core-shell nanosonosensitizer (TiO2@CaP) that reinvigorates ROS generation and dissolves its CaP shell to release Ca2+ in an acidic tumor microenvironment (TME) under ultrasound activation. Thus, TiO2@CaP acts as a smart nanosonosensitizer that specifically induces mitochondrial dysfunction via overloading intracellular Ca2+ ions to synergize with the sonodynamic process in the TME. TiO2@CaP substantially enhances immunogenic cell death, resulting in enhanced T-cell recruitment and infiltration into the immunogenic cold tumor (4T1). In conjunction with checkpoint blockade therapy (anti-PD 1), TiO2@CaP-mediated sonodynamic therapy elicits systemic antitumor immunity, leading to regression of non-treated distant tumors and inhibition of lung metastasis. This work paves the way to development of smart TME-activatable sonosensitizers with temporospatial control over antitumor responses.

Automated summary

The study introduces a smart nanosonosensitizer TiO2@CaP which enhances the generation of reactive oxygen species (ROS) under ultrasound activation, inducing mitochondrial dysfunction in the tumor microenvironment and promoting immunogenic cell death, resulting in T-cell infiltration and systemic antitumor immunity. This approach holds promise for developing TME-activatable sonosensitizers with temporospatial control over antitumor responses.