Construction of BowtieCyclophane from Inherent Charged AIEgens for Two-Photon Excited Fluorescence and Supramolecular Drug Delivery

Supramolecular drug delivery systems (DDS) have emerged as promising platforms to address the limitations of conventional insoluble drugs. Despite the fact that macrocyclic hosts including cyclodextrins and pillararenes were demonstrated to be favorable for improved drug solubility and controlled release, their rigid cavities generally fail to accommodate structurally complex therapeutics or enable real-time tracking. Herein, we report the construction of a tetracationic tetraphenylethylene-derived BowtieCyclophane ( M s,s-chda ) featuring (1) strong aggregation-induced emission (AIE) and two-photon excited fluorescence (TPEF) with a cross section of 36,740 GM, (2) enhanced cellular uptake efficiency through inherent charged cationic surfaces, and (3) adaptive cavity flexibility to form a 1:1 stoichiometry host–guest complex with 10-hydroxycamptothecin (HCPT) and targeted delivery into the lysosome of tumor cells for in situ imaging and monitoring. Furthermore, the biocompatible host–guest complex manifests enhanced cytotoxicity alongside deep-tissue two-photon imaging ability of 300 μm live tumor spheroids compared with bare HCPT. This work provides the integration of AIE-active and two-photon excited flexible macrocycles with topoisomerase inhibitors, establishing an all-in-one strategy for deeper tissue imaging, drug delivery, and chemotherapy based on supramolecular chemistry.