Usnea Acid‐Incorporated Ca²⁺/Mn²⁺ Ions Reservoirs for Elevated Ion‐Interference Therapy through Synergetic Biocatalysis and Osmolarity Imbalance

Abstract Ion‐interference therapy (IIT) utilizes ions to disturb intracellular biological processes and has been received increasing attention in tumor treatments recently. However, the low therapeutic efficiency still hinders its further biological applications. Herein, via a simple and one‐pot gas diffusion process, polyethylene glycol (PEG)‐modified Mn²⁺ ions and usnic acid (UA)‐incorporated CaCO₃ nanomaterials (^PEGCaMnUA) as Ca²⁺/Mn²⁺ ions reservoirs are prepared for magnetic resonance imaging (MRI)‐guided UA‐elevated IIT. Among ^PEGCaMnUA, UA not only increases cytoplasmic Ca²⁺ ions to amplify Ca²⁺ overload caused by CaCO₃ decomposition, but also enhances Mn²⁺ ions‐participated Fenton‐like biocatalysis by intracellular H₂O₂ generation and glutathione consumption. Then increasing the intracellular oxidative stress and decreasing the triphosadenine supply induce apoptosis together, resulting in UA‐boosted IIT. The simple and efficient design of the dual ions reservoirs will contribute to improve the antitumor activity of IIT and further development of calcium‐based nanomaterials in the future.