High Drug Loading Pillar[5]Arene‐Based Nanodrug Delivery System Enhances Anticancer Efficacy and Reduces Toxicity

Abstract Nanodrug delivery is a critical approach in cancer therapy; however, the deposition of excipients often exacerbates the toxic burden of drugs. Herein, a pillar[5]arene‐based supramolecular nanodrug delivery system (WP5⊃C6Py@DOX) has been developed to enhance cancer therapy efficacy while minimizing side effects. This system, constructed through host–guest interactions between a thioether‐modified pillar[5]arene derivative (WP5) and a pyridinium salt derivative (C6Py), exhibited a remarkable 97% drug loading capacity for doxorubicin (DOX). It showed remarkable stability in both aqueous solutions and bovine serum, effectively minimizing premature drug leakage and reducing associated toxicity. The thioether modification of WP5 reacted with H 2 O 2 to generate derivatives with improved water solubility, significantly enhancing biocompatibility while minimizing excipient deposition within endosomes. Cellular experiments revealed that the system not only reduced the toxicity of DOX to normal cells (BEAS‐2B) but also significantly enhanced its antitumor activity against cancer cells (HepG2), with an IC 50 of 1.2 µ m , markedly outperforming free DOX (IC 50 : 6.3 µ m ). Furthermore, laser confocal imaging confirmed that the supramolecular drug delivery system effectively enters and accumulates in cancer cells, demonstrating promising therapeutic potential.