Bufalin CaCO Nanoparticles Triggered Pyroptosis through Calcium Overload via Na/Ca Exchanger Reverse for Cancer Immunotherapy.

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 nanoparticle hydrogel, for enhancing cancer treatment through inducing cellular pyroptosis. Under the tumor microenvironment's low pH conditions, bufalin and Ca are released from the delivery system. Bufalin serves as a direct anticancer drug and a Na/K-ATPase inhibitor by forcing the Na/Ca exchanger to reverse its function, which transfers Ca into cytoplasm and ultimately causes Ca 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.