A Strategy to Induce Calcium Ion Storm in Cancer Stem Cells for Efficient Cancer Therapy

Currently, tumor treatment strategies centered on Ca²⁺ homeostasis imbalance primarily target mature tumor cells while neglecting the eradication of cancer stem cells (CSCs), which results in the long-standing unresolved challenge of tumor relapse in later stages of treatment. To tackle the challenge, a calcium peroxide nanoparticle (CPN)-based strategy aimed at inducing an intracellular calcium ion storm in CSCs for efficient cancer therapy was proposed in this study. Typically, hyaluronic acid (HA)-stabilized hollow mesoporous calcium peroxide nanoparticles (HMCPN@HA4) were synthesized via a facile hydrolysis-precipitation method. Under an acidic tumor microenvironment (TME), 5(6)-carboxyeosin (CE)-loaded HMCPN@HA4 (HMCPN-CE3@HA4) degrades to release Ca²⁺, hydrogen peroxide (H₂O₂), and CE. CE impedes the cellular efflux of calcium ions, resulting in a state in which Ca²⁺ flows only into the cell and does not outflow (only in, not out), thereby inducing a calcium ion storm. These released components collectively promote ferroptosis and calcioptosis in tumor cells through Fenton reactions and Ca²⁺ storms, thereby effectively eliminating both CSCs and mature tumor cells. In vitro experimental results show that HMCPN-CE3@HA4 can significantly inhibit the stemness of MOC1 side population (SP) stem cells and produce significant toxicity, resulting in nearly 80% cell death. After intravenous administration, HMCPN-CE3@HA4 exhibits superior antitumor efficacy and excellent biosafety.