Review Supramolecular nano drug delivery systems mediated via host-guest chemistry of cucurbit[n]uril (n = 6 and 7) Shengke Li a, * , 1 , Yan Gao b, 1 , Yuanfu Ding b , Anni Xu a , Huaping Tan a a School of Materials Science and Engineering, Nanjing University of Science and Technology, Nanjing 210094, China b State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China A R T I C L E I N F O Article history: Received 12 March 2020 Received in revised form 15 April 2020 Accepted 27 April 2020 Available online xxx Keywords: Cucurbit[n]uril Host-guest chemistry Self-assembly Nano Drug delivery Stimuli-responsive A B S T R A C T As a novel family of macrocyclic molecules, cucurbit[n]urils (CB[n]s) have emerged as promising building blocks of supramolecular nano drug delivery systems (SNDDS) in recent years. Direct encapsulation of amphiphilic guests by CB[6] and CB[7] can modulate their amphiphilicity, resulting in formation of supramolecular amphiphiles that self-assemble into supramolecular nanoparticles for drug delivery. Additionally, CB[n]’s host-guest chemistry on the surface of mesoporous nanoparticles makes CB[n] an ideal blocking agent to control drug release from delivery vehicles. These SNDDS possess intrinsic stimuli responsiveness towards external guest or host, which can further incorporate responsiveness to a variety of other stimuli including pH, thermal, redox, photo and enzyme, to realize multiple stimuli-responsive drug release. Moreover, the recent breakthrough in direct functionalization of CB[n]s has provided a feasible method for preparing superior CB[6] and CB[7] derivatives that can be employed to build multifunctional SNDDS with unoccupied macrocycles located on surface, which could be decorated with various functional “tags” through host-guest chemistry. In this review, we summarized the recent progress of CB[6] and CB[7] based SNDDS through formation of supramolecular amphiphiles, supramolecular nanovalves as well as supramolecularly tailorable surface, which we hope to further promote the development of CB[n]s family as building blocks for advanced SNDDS. © 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved. 1. Introduction Supramolecular architectures often rely on dynamic non- covalent interactions, including hydrogen bonding, electrostatic interaction, ion-dipole/dipole-dipole interactions, hydrophobic interaction, p-p stacking, and host-guest interaction [1–3]. Among them, macrocycle based host-guest interaction has been consid- ered as a versatile solution to construct multifunctional, reversible supramolecular assemblies for various fascinating applications [4– 8]. Cucurbit[n]urils (CB[n]s, n = 5–8, 10) are condensation products between glycoluril and formaldehyde in strong acidic solutions, forming rigid macrocycles with n glycoluril units linked by 2n methylene groups at each side [9–11]. The rigidity of CB[n] macrocycles endows CB[n]s remarkable thermal and chemical stability, however it also makes it challenging to introduce functional groups onto CB[n]s molecules [12]. The most attracting feature of CB[n]s is their strikingly high affinity and selectivity towards encapsulated guests in an aqueous solution, resulting from synergistic contributions of hydrophobic effect inside cavity and ion-dipole interactions adjacent to carbonyl portal [10, 13, 14]. Zhang et al. and Xu et al. have developed a plethora of inspiring supramolecular assemblies for efficient supramolecular chemo- therapy of cancer via CB[n]-mediated host-guest chemistry [15– 17]. In addition, CB[n]-based supramolecular antibiotics were also pioneered with a great success [18–20]. CB[n]-mediated host- guest chemistry also has been extensively investigated in construction of supramolecular nano drug delivery systems (SNDDS) [4, 10, 14,21–23]. For instance, CB[6]’s encapsulation of an amphiphilic molecule was found to significantly decrease its critical micelle concentration (CMC), resulting in the formation of supramolecular nanoparticles for drug delivery at much lower concentrations [24]. Additionally, CB[7]-mediated supramolecular (pseudo)rotaxanes were also employed to build responsive nano- valves for the controlled release of cargoes from mesoporous nanoparticles [25]. The unique ability of CB[8] in forming stable ternary complexes by simultaneous encapsulation of two guests into its cavity makes CB[8] an ideal molecular “glue or handcuff” to construct various supramolecular drug delivery vehicles including supramolecular vesicles, supramolecular organic framework and * Corresponding author. E-mail address: lisk@njust.edu.cn (S. Li). 1 These two authors contributed equally to this work. https://doi.org/10.1016/j.cclet.2020.04.049 1001-8417/ © 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved. Chinese Chemical Letters xxx (2019) xxx–xxx G Model CCLET 5628 No. of Pages 6 Please cite this article in press as: S. Li, et al., Supramolecular nano drug delivery systems mediated via host-guest chemistry of cucurbit[n]uril (n = 6 and 7), Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.04.049 Contents lists available at ScienceDirect Chinese Chemical Letters journal homepa ge: www.elsevier.com/locate/cclet