Spatial order of functional modules enabling diverse intracellular performance of fluorescent probes.

To overcome a series of challenges in tumor therapy, modular-agent probes (MAPs) comprised of various functional modules have been proposed. Nowadays, researchers have tried to optimize the MAPs by exploiting the new modules or increasing the numbers of module, while neglecting the configuration of various modules. Here, we focus on the different spatial-arrangements of existing modules. By utilizing a tetraphenylethylene (TPE) derivative with stereochemical structure and dual modifiable end-group sites as small molecule scaffold, two MAPs with same modular agents (module T for enhancing the internalization of MAPs by tumor cells and module M for causing mitochondrial dysfunction) but different spatial-arrangements (on the one side, TM-AIE, and two sides, T-AIE-M, of the molecule scaffold) are designed. It was found that T-AIE-M with bigger RGD binding angle performed higher specificity, while TM-AIE characterizing longer α-helix structure displayed superior toxicity. This interesting phenomenon sheds light on the design concept of future MAPs and opens a window for the renaissance of existing MAPs by rearranging modules.