In Situ Activation of the Receptor Aggregation for Cell Apoptosis by an AI-Au Intelligent Nanomachine via Tumor Extracellular Acidity

Polyvalent ligand-induced cell receptoraggregation is closelyrelated to cell behavior regulation. At present, most of the meansto induce receptor aggregation rely on external stimuli such as light,heat, and magnetic fields, which may cause side effects to normalcells. How to achieve receptor aggregation on the cancer cell surfaceto achieve cell apoptosis selectively is still a challenge. Therefore,by taking advantage of the unique property of cancer cells'slightly acidic microenvironment, an easy-to-use apoptosis-inducingmode for the in situ activation of cell surface nucleolin clusteringhas been developed, which not only opened a new channel for nucleolinreceptor aggregation to regulate cell function and further developmentbut also avoided damage to normal cells, providing a new strategyfor tumor treatment. Dual functional ssDNA (AS1411 aptamer and pH-responsiveI-strand sequence) was modified on the surface of gold nanoparticles(AuNPs) to fabricate AI-Au intelligent nanomachines. Then,the specific binding on cancer cells and aggregation of the nucleolinreceptors can be achieved via the formation of an i-Motif structureamong adjacent AuNPs under the acidic microenvironment. The resultshowed that AI-Au nanomachines mediated nucleolin cross-linkingon the cell surface, resulting in a cytotoxic effect of approximately60%. Experiments such as calcein-AM/PI staining, nuclear dye staining,and flow cytometry demonstrated that cell apoptosis became more evidentwith the increase of acidity under the cell surface microenvironment.Immunofluorescence imaging further confirmed the Cyt-c/caspase-3 apoptosispathway induced by AI-Au nanomachines. The proposed strategyused for specific cancer cell apoptosis by the in situ activationof tumor cell membrane receptor aggregation is inexpensive and simpleto use, which not only provides a new means of nucleolin receptoraggregation for regulating cell function but also offers a new strategyfor tumor treatment with reduced side effect to normal cells. Thiswork is significant for comprehending the ligand-induced receptoraggregation process and can lead to the development of a promisinganticancer drug.

Automated summary

A simple and cost-effective method has been developed to selectively induce cancer cell apoptosis by activating cell surface nucleolin clustering in the slightly acidic microenvironment of cancer cells. This strategy not only regulates cell function through nucleolin receptor aggregation, but also provides a new approach for tumor treatment with reduced side effects to normal cells.