Biodegradable Ca-MOF Nanoplatform with Intracellular H₂O₂-Triggered CO Release to Augment Mitochondrial Ca²⁺ Overload for Synergistic Cancer Therapy

To address the challenges of precise calcium regulation and limited efficacy in MOF-based nanomedicine, we developed a biodegradable Ca-MOF platform (Ca-MOF@MnCO/HA) coated with hyaluronic acid (HA) and loaded with a H₂O₂-responsive CO prodrug, manganese carbonyl (MnCO). This system enables CD44-mediated tumor targeting, followed by acid-triggered biodegradation in the tumor microenvironment (TME) to release Ca²⁺ and MnCO. Intracellular H₂O₂ then promotes CO release, inducing mitochondrial dysfunction and impairing calcium efflux. The concurrent release of Ca²⁺ and CO causes sustained calcium overload, intensifying oxidative stress, activating apoptosis, and triggering tumor-specific calcification. This gas-ion synergy highlights the potential of programmable inorganic nanomedicines for improved anticancer therapy.