Double-layer Infinite Coordination Polymer Nanocomposites for Large Tumor Elimination in Mice via Electrothermal-thermodynamic-chemo Trimodal Powerful Networked Multiple Synergistic Therapy

To further enhance the comprehensive synergistic therapeutic effect for large tumor, we developed a strategy of electrothermal-thermodynamic-chemo trimodal networked multiple synergistic therapy utilizing four therapeutic agents. Double-layer infinite coordination polymer (ICP) nanocomposites (ICPs-1@ICPs-2 CNPs) were prepared to implement the strategy, in which hypoxia-activated AQ4N and thermodynamic agent AIPH coordinated with Cu(Ⅱ) to form initial layer of positively charged ICPs-l NPs, chemotherapeutic agents gossypol-hyaluronic acid (G-HA) and CA4 coordinated with Fe(Ⅲ) to form out layer of negatively charged ICPs-2 NPs, and then double-layer ICPs-1@ICPs-2 CNPs were fabricated by electrostatic adsorption using ICPs-l NPs and ICPs-2 NPs. Notably, the number of therapeutic agents from three to four results in a noteworthy augmentation of synergistic effects. The whole synergies among the four therapeutic agents are analogous to a three-dimensional regular tetrahedron, yielding a total of 29 networked synergies during the three-stage therapeutic procedures under the thermal stimulation of micro-electrothermal needle (MEN). The resulting nanocomposites demonstrate a powerful networked multiple synergistic therapeutic outcomes for large tumors with lower dosage, achieving a tumor inhibition rate nearly reaching 100 % and no recurrence for 60 days. This study presents a remarkable advantage that could potentially provide the new way for tumor synergistic therapy in future.