A Pillar[5]Arene-Based Supramolecular Nanoplatform With Dual Stimuli-Responsiveness for Targeted and Traceable Cancer...

The development of a functionalized nanodrug delivery system (NDDS) represents a critical strategy in cancer diagnosis and therapy; however, smart materials capable of simultaneously tracking drug uptake and enabling targeted therapeutic intervention remain urgently needed. Herein, we designed a supramolecular NDDS, WP5@2G@DOX@HA, which was constructed via the co-assembly driven by host-guest interactions between a water-soluble pillar[5]arene (WP5) host and two differently functionalized pyridinium-based guest molecules (TPP and TPE), followed by surface modification with hyaluronic acid (HA). This system exhibits a high drug loading capacity, sensitive dual pH/Ca²⁺ responsiveness, and effective targeting ability, while reducing its toxicity toward normal cells. Furthermore, in vitro fluorescence imaging confirmed that the cyan fluorescence from the TPE component was internalized by 4T1 cells, allowing for monitoring of the NDDS uptake. Mitochondrial membrane potential fluorescent probe (JC-10) assays demonstrated that the incorporated TPP component promoted mitochondrial membrane potential depolarization in cancer cells, thereby inducing apoptosis. Thus, WP5@2G@DOX@HA integrates the unique therapeutic potential of the two functionalized guest molecules in a simple and efficient manner, providing a new paradigm for the design of multifunctional NDDS.