Bufalin CaCO<sub>3</sub> Nanoparticles Triggered Pyroptosis through Calcium Overload via Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger Reverse for Cancer Immunotherapy
Tingxuan Li, Yitong Zhang, Hanyue Li, Hanjie Zhang, Juntao Xie, Zimu Li, Kai Zhang, Yongkang Yu, Lin Mei
Abstract
Bufalin is a promising active ingredient in traditional Chinese medicine but has shown limited anticancer applications due to its toxicity. Here, we report BCNPs@gel, a bufalin-containing CaCO 3 nanoparticle hydrogel, for enhancing cancer treatment through inducing cellular pyroptosis. Under the tumor microenvironment’s low pH conditions, bufalin and Ca 2+ are released from the delivery system. Bufalin serves as a direct anticancer drug and a Na + /K + -ATPase inhibitor by forcing the Na + /Ca 2+ exchanger to reverse its function, which transfers Ca 2+ into cytoplasm and ultimately causes Ca 2+ overload-triggered pyroptosis. Meanwhile, we found that bufalin can upregulate PD-L1 in tumor cells. In combination with the PD-1 antibody, the delivery system showed a greater performance during the cancer treatment. BCNPs@gel enhances antitumor efficiency, reduces systemic side effects, extends antitumor mechanism of bufalin, and provides new strategies for inducing pyroptosis and calcium overload in cancer immunotherapy via Na + /K + -ATPase inhibitor. This work provides an application model for numerous other traditional Chinese medicine ingredients.