Crystal-Phase Engineering Enables Al3+ Liberation from Nanoclay for Ion Interference Tumor Therapy

Ion interference therapy (IIT) has emerged as a promising antitumor strategy by disrupting intracellular ion homeostasis. However, balancing physiological ion stability with tumor-responsive ion release remains a critical challenge. Herein, we present a crystal-phase engineering approach to program montmorillonite nanoclay with thermally responsive lattice strain, which enables tumor microenvironment (TME)-triggered crystal-phase aluminum (Al) liberation. Hyperthermia-induced lattice distortion amplifies the surface Al-OH density by 1.7-fold, promoting pH-responsive crystal-phase Al liberation in the acidic TME. Systematic investigations reveal that the engineered nanoclay maintains physiological stability while achieving 87.5% tumor-selective crystal-phase Al liberation (increased by 70%), which destroys tumor cell membranes by interacting with membrane phospholipids, thereby accelerating intracellular uptake. Furthermore, the intracellular liberation of crystal-phase Al causes mitochondrial dysfunction through oxidative stress, ultimately inducing tumor cell death and awakening the systemic immune response. This work pioneers crystal-phase modulation in nanoclay-based therapeutics, providing a roadmap for the development of spatially controlled ion interference agents.