A bufalin and CRISPR/Cas9 ribonucleoprotein-loaded calcium lactate nanomedicine for pyroptosis/apoptosis and synergistic cancer immunotherapy

作者：Yichen Liu, Dahai Hou, Hui Wang, Qiuying Yan, Yunzhu Xu, Qibiao Wu, Dan Hong Dong, Weixing Shen, Weiwei Tao, Haibo Cheng, Dongdong Sun · 发表于：Materials Today Bio · 年份：2025 · DOI：10.1016/j.mtbio.2025.102527 · 被引用次数：2 · 研究领域：Immune cells in cancer、interferon and immune responses、Phagocytosis and Immune Regulation

Colorectal cancer, a highly invasive malignancy, poses significant treatment challenges due to the immunosuppressive tumor microenvironment. Tumor-associated macrophages, which primarily exhibit the M2 phenotype, play a key role in cancer progression and immune evasion. Reprogramming these M2 macrophages to the tumor-suppressive M1 phenotype represents a promising therapeutic approach to enhance antitumor immunity. In this study, we developed a calcium lactate nanoparticle-based delivery system (CLBRP) to codeliver bufalin, a potent Na + /K + -ATPase inhibitor with anticancer properties, and CRISPR-Cas9, which targets the immune checkpoint CD47. The system releases its payload under low pH conditions typical of the tumor microenvironment, increasing extracellular Ca 2+ and intracellular osmotic pressure, thereby inducing pyroptosis and immunogenic cell death. Bufalin induces cancer cell apoptosis, inhibits Na + /K + -ATPase, and triggers pyroptosis, which activates a strong immune response. Additionally, bufalin and D-lactic acid synergistically promote macrophage repolarization to the M1 phenotype. CRISPR-Cas9-mediated editing of the CD47 gene on tumor cells blocks antiphagocytic signals, enhancing M1 macrophage phagocytosis and increasing the antitumor immune response. This multimodal strategy triggers strong local antitumor effects and controls metastatic lesions via systemic immune activation, demonstrating significant potential for colorectal cancer treatment. Furthermor...