A pillar[5]arene-based hyaluronic acid-decorated amorphous bimetallic metal-organic framework for multimodal synergistic cancer therapy.

Current antitumor monotherapies have many limitations, and developing novel synergistic anticancer strategies with low side effects and high antitumor efficiency remains a significant challenge. Herein, we developed a pH and GSH dual-responsive pillar[5]arene-based amorphous bimetallic metal-organic framework (DOX@Fe/CuP5H) for synergistic antitumor therapy involving ferroptosis, cuproptosis and apoptosis. The hydrazide-functionalized pillar[5]arene derivatives were coordinated with Cu2+ to form irregular nanoparticles, which were subsequently etched and surface-coordinated using Fe3+. Finally, doxorubicin (DOX) was loaded onto the structures, followed by surface decoration with hyaluronic acid (HA) to yield the multifunctional DOX@Fe/CuP5H. The porous structure and amorphous nature of Fe/CuP5, and the specific binding of HA to CD44 overexpressed in cancer cells endowed the DOX@Fe/CuP5H with a high drug-loading capacity and effective targeting ability, while simultaneously reducing its toxicity to normal cells. DOX@Fe/CuP5H can dissociate in the tumor microenvironment, rapidly releasing DOX to induce apoptosis. Excess Fe3+ and Cu2+ deplete intracellular GSH, leading to a redox imbalance. The accumulation of Fe2+ further promotes the production of reactive oxygen species (ROS) and lipid peroxide (LPO), triggering ferroptosis. Additionally, FDX1 regulates cellular protein lipoylation, while Cu+ binds to lipoylated proteins, causing acute proteotoxic stress and inducing cellular cuproptosis. Therefore, the rationally designed pillar[5]arene-based amorphous bimetallic metal-organic framework provides a safe and high-performance platform for enhancing the efficacy of multimodal synergistic anticancer therapies.