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

Currently, tumor treatment strategies centered on Ca 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 Ca, hydrogen peroxide (HO), and CE. CE impedes the cellular efflux of calcium ions, resulting in a state in which Ca 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 Ca storms, thereby effectively eliminating both CSCs and mature tumor cells. 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.