CaCO₃ nanoparticles incorporated with KAE to enable amplified calcium overload cancer therapy

Calcium overload therapy has attracted widespread attention in oncological field, whereas its efficacy has been limited due to insufficient calcium ions in tumor site and poor efficiency of calcium entering tumor, resulting in dissatisfied therapeutic effect. Kaempferol-3-O-rutinoside (KAE), a biosafe flavone with excellent anti-cancer ability, can effectively disrupt calcium homeostasis regulation and facilitate calcium influx, while calcium carbonate (CaCO₃) serves as an ideal calcium ions supplier. Inspired by these concepts, KAE loaded into CaCO₃ nanoparticles and incorporated with the cancer cell membrane (M) for synergistic tumor therapy. In this therapeutic platform (M@CaCO₃@KAE), membrane coating ensures targeted delivery of CaCO₃@KAE. Upon reaching tumor, CaCO₃@KAE specifically responds to tumor microenvironment, consequently releases KAE and calcium ions. KAE effectively breaks the calcium balance, while calcium ions remarkably aggravate and magnify KAE-mediated calcium overload. Accordingly, mitochondrial structure and functions are destructed, causing cytoskeleton collapse and oxidative stress, leading to cancerous cellular apoptosis. With the combined and cascaded efficacy, considerable in vitro and in vivo tumor inhibition was achieved by M@CaCO₃@KAE. This study provides an alternative nano-system, acting as a biomimetic calcium bomb, to ensure targeted, synergistic, efficient and biosafe calcium overload tumor therapy.