Site-Specific Location of Black Phosphorus Quantum Dot Cluster-Based Nanocomplexes for Synergistic Ion Channel Therapy and Hypoxic Microenvironment Activated Chemotherapy

The spatiotemporal regulation of ion transport in living cell membrane channels has immense potential for providing novel therapeutic approaches for the treatment of currently intractable diseases. So far, most strategies suffer from uncontrolled ion transport and limited tumor therapy effects. On the premise of low toxicity to healthy tissues, enhancing the degree of ion overloading and the effect of tumor treatment still remains a challenging concern. Herein, an innovative strategy for synergistic ion channel therapy and hypoxic microenvironment activated chemotherapy is proposed. Biocompatible AQ4N/black phosphorus quantum dot clusters@liposomes (AQ4N/BPCs@Lip) nanocomplexes are site-specifically immobilized on the living cell membrane by a metabolic labeling strategy, eliminating the need for modifying or genetically encoding channel structures. Ascribing to the localized temperature increase of BPCs under NIR light irradiation, Ca²⁺ overinflux can be remotely controlled and the overloading degree was increased; moreover, the local released AQ4N can only be activated in the tumor cell, while it has no toxicity to normal cells. Compared with single intracellular Ca²⁺ overloading, the tumor cell viabilities decrease 2-fold with synergetic Ca²⁺ overloading-induced ion channel therapy and hypoxic microenvironment activated chemotherapeutics. Our study demonstrates the example of a remote-controlled ion influx and drug delivery system for tumor therapy.