The swelling-shrinking transition of hydrogels is crucial for their wide applications such as actuators and drug delivery. We hereby fabricated a smart hydrogel with ferrocene groups on pendant of polymer networks. While it was immersed in the water-soluble pillar[6]arene (WP6) aqueous solution, the hydrogel was dramatically swollen, which was an approximately 11-fold promotion in weight compared with that in pure water, due to the formation of the inclusion complexes between WP6 and ferrocene groups in the hydrogel. In particular, the well-swollen hydrogel exhibited good responsiveness to multistimuli including temperature, pH, redox, and competitive guests by tuning the dissociation/formation of WP6-ferrocene inclusion complexes or the strength of their charges. Meanwhile, potential application of such a smart hydrogel in pH-responsive drug release was demonstrated as well.

A dual-responsive supramolecular network based on pillar[6]arene−ferrocenium redox-controllable recognition motifs in polymeric backbones is constructed with a ferrocenium-functionalized copolymer and a pillar[6]arene copolymer, in which the first example of pillar[6]arene-functionalized copolymer was synthesized through the reversible addition/ fragmentation chain-transfer copolymerization of an acrylate-functionalized pillar[6]arene and methyl acrylate. The resulting supramolecular network exhibits dramatically increased viscosity than the non-cross-linked mixtures and demonstrates a gel-like behavior on macroscale with a transient-network behavior revealed by rheology study. Furthermore, the viscoelastic properties of such supramolecular network can be easily controlled by different external stimuli including redox stimulus and competing host/ guest reagents.

The controllable construction of biocompatible supramolecular nanocarriers with different morphologies based on dynamic noncovalent interactions to achieve selective delivery of drugs with different properties remains highly challenging. We herein report controllable construction of two types of supramolecular nanocarriers based on biocompatible water-soluble phosphate-based pillar[5]­arene (WP5P) or pillar[6]­arene (WP6P) with pyridinium bromide guest G for the selective anticancer drug delivery. Solid supramolecular micelles could be obtained by the amphiphilic host–guest inclusion complex formed from WP5P and G, whereas hollow supramolecular vesicles were acquired from WP6P and G. Both of them showed pH- and Zn2+-responsiveness. Furthermore, the resulting solid micelles were able to encapsulate hydrophobic anticancer drug doxorubicin (DOX) to achieve DOX-loaded micelles, while hydrophilic anticancer drug mitoxantrone (MTZ) could be successfully loaded into the hollow vesicles. Additionally, the encapsulated anticancer drugs could be efficiently released at low-pH environment or with the introduction of Zn2+. More importantly, cytotoxicity experiments indicated that these water-soluble phosphate-based pillar­[5,6]­arenes showed excellent biocompatibility, and the drug-loaded nanoparticles exhibited comparable therapeutic effect for cancer cells as free anticancer drugs and remarkably reduced damage for normal cells as well. Cellular uptake and intracellular localization experiments further confirmed that these two types of nanocarriers, taken up by cancer cells via endocytosis, could lead to efficient drug accumulation in cancer cells. Therefore, this strategy of controllable construction of different types of stimuli-responsive supramolecular nanocarriers based on biocompatible phosphate-based pillar­[5,6]­arenes have great potential applications in the field of controlled drug delivery.

Supramolecular construction of a targeted and stimuli-responsive drug delivery system is still a challenging task. Herein, GSH-responsive supramolecular prodrug nanoparticles were constructed by the host-guest complexation between a β-d-galactose-functionalized water-soluble pillar[5]arene (GalP5) and a disulfide bond containing camptothecin prodrug (G). The obtained prodrug nanoparticles were stable under physiological conditions, whereas efficient drug release was triggered in a simulated tumor environment with high GSH concentration. In vitro studies revealed that these prodrug nanoparticles preferentially entered asialoglycoprotein receptor-overexpressing HepG2 cells due to the active targeting effect of galactose units. This active targeting effect resulted in the maximization of anticancer efficacy and reduction of the undesirable side effects to normal cells.

Supramolecular construction of multistimuli platform for drug delivery is a challenging task. In this work, a pH and GSH (glutathione) dual-responsive bola-type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene (WP5) and a bolaform naphthalimide guest (G) in water. The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles, which could be disassembled by low pH, a high-GSH-concentration environment, or both. Furthermore, the results of drug loading and releasing tests showed that doxorubicin (DOX), the hydrophobic anticancer drug, could be successfully encapsulated into the Stern region of the obtained supramolecular vesicles and generated the DOX-loaded vesicles with good drug-loading efficiency. Moreover, the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH or excess-GSH conditions or both. Significantly, cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells while remarkably reducing its side effects for normal cells. In vitro cellular uptake and subcellular localization assays further proved that these smart drug nanovehicles, entering cancer cells mainly via endocytosis, could cause excellent drug accumulation in cancer cells. The present study provides a successful example with which to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier, which might have wide potential applications in the construction of various controlled drug-delivery systems.