Luminescent Nanocucurbits Enable Spatiotemporal Co‐Delivery of Hydrophilic and Hydrophobic Chemotherapeutic Agents

Abstract The generation of nanostructures with asymmetric morphologies has garnered significant attention in nanomedicine research, particularly since morphological characteristics have been shown to critically influence the biological functionality. Herein, the rational design and successful fabrication of luminescent cucurbit‐shaped nanoparticles (nanocucurbits) is presented for co‐delivery of hydrophilic and hydrophobic chemotherapeutic agents. These innovative nanostructures are obtained through the self‐assembly of a tetraphenylethylene (TPE)‐graft polypeptide copolymer, poly(ethylene glycol) 45 ‐ block ‐poly[(L‐glutamic acid‐TPE) 26 ‐ stat ‐(L‐glutamic acid) 29 ] [PEG 45 ‐ b ‐P(GATPE 26 ‐ stat ‐GA 29 )], employing an optimized solvent‐switch method. Remarkably, these nanocucurbits exhibit a dramatically enhanced uptake level of which the total amount of intracellular endocytosis is about two‐fold higher than that of the spherical counterparts. Capitalizing on this distinctive asymmetric structure, the nanocucurbits exhibit an exceptional dual‐loading capability, enabling the simultaneous encapsulation of both hydrophilic (doxorubicin hydrochloride, DOX) and hydrophobic (camptothecin, CPT) agents. The co‐delivery of dual‐drugs within the same carrier, along with the sequential release of the drug combination, enables this drug delivery system with synergistic chemotherapeutic effect against hepatoma cells. Overall, the unique combination of morphological advantages, intrinsic luminescence, and dual‐drug loading capability renders these nanocucurbit‐based system a promising platform for multi‐agent combination therapy, particularly in cancer treatment requiring the simultaneous delivery of drugs with distinct physicochemical properties.