Multienzyme-Mimicking LaCoO3 Nanotrigger for Programming Cancer-Cell Pyroptosis

Pyroptosis, a distinct paradigm of programmed cell death, is an efficient strategy against cancer by overcoming resistance to apoptosis. In this study, LaCoO3 (LCO) lanthanide-based nanocrystals with multienzyme characteristics are rationally designed and engineered to trigger the generation of cytotoxic reactive oxygen species (ROS) and the release of lanthanum ions, ultimately inducing lung cancer cell pyroptosis. The peroxidase- and oxidase-mimicking activities of LCO nanocrystals endow LCO with ROS production capacity in tumor tissues with an acidic pH and high hydrogen peroxide content. Concurrently, the LCO nanoenzyme exhibits catalase- and glutathione peroxidase-like activities, reversing the hypoxic microenvironment, destroying the activated antioxidant system of tumor cells, and amplifying the sensitivity of tumor cells to ROS. The use of ultrasound further accelerates the enzymatic kinetic rate. Most importantly, the La3+ ions released by LCO robustly destroy the lysosomal membrane, finally inducing canonical pyroptotic cell death, together with ROS. LCO-nanocrystal-triggered programmed cell pyroptosis amplifies the therapeutic effects both in vitro and in vivo, effectively restraining lung cancer growth and metastasis. This study paves a new avenue for the efficient treatment of lung cancer and metastasis through US-enhanced lanthanum-based nanoenzyme platforms and pyroptotic cell death.

Automated summary

In this study, LaCoO3 (LCO) lanthanide-based nanocrystals were designed to trigger lung cancer cell pyroptosis by generating cytotoxic reactive oxygen species (ROS) and releasing lanthanum ions. The LCO nanoenzyme exhibited peroxidase- and oxidase-mimicking activities, producing ROS in the tumor microenvironment. It also reversed the hypoxic environment, destroying the antioxidant system of tumor cells and increasing their sensitivity to ROS. LCO-induced pyroptotic cell death effectively restrained lung cancer growth and metastasis.