Nanoscale Advances View Article Online REVIEW View Journal | View Issue Nanoscale covalent organic frameworks as theranostic platforms for oncotherapy: synthesis, Cite this: Nanoscale Adv., 2020, 2, 3656 functionalization, and applications Qun Guan, Guang-Bo Wang,* Le-Le Zhou, Wen-Yan Li and Yu-Bin Dong * Cancer nanomedicine is one of the most promising domains that has emerged in the continuing search for cancer diagnosis and treatment. The rapid development of nanomaterials and nanotechnology provide a vast array of materials for use in cancer nanomedicine. Among the various nanomaterials, covalent organic frameworks (COFs) are becoming an attractive class of upstarts owing to their high crystallinity, structural regularity, inherent porosity, extensive functionality, design flexibility, and good biocompatibility. In this comprehensive review, recent developments and key achievements of COFs are provided, including their structural design, synthesis methods, nanocrystallization, and functionalization Received 28th June 2020 strategies. Subsequently, a systematic overview of the potential oncotherapy applications achieved till Accepted 15th July 2020 Creative Commons Attribution 3.0 Unported Licence. date in the fast-growing field of COFs is provided with the aim to inspire further contributions and DOI: 10.1039/d0na00537a developments to this nascent but promising field. Finally, development opportunities, critical challenges, rsc.li/nanoscale-advances and some personal perspectives for COF-based cancer therapeutics are presented. 1 Introduction turned their research interest towards rational designing and preparation of nanopharmaceuticals for tumor diagnosis and – Cancer remains a worldwide public health issue with high treatment3 6 due to drawbacks in conventional therapies, such morbidity and mortality rates.1 It is estimated that by 2030, the as chemotherapy, radiotherapy, and surgical resection.7 This article is licensed under a number of cancer cases will increase to 24.6 million, while the Nanoparticle-based drug delivery, which integrates emerging number of cancer deaths can reach around 13 million.2 In nanotechnologies with traditional chemotherapeutic drugs to recent years, increasing number of researchers in the elds of get rid of drawbacks in traditional therapies as well as offer new possibilities to optimize cancer treatment, has always been one Open Access Article. Published on 16 July 2020. Downloaded 10/10/2021 9:30:22 AM. chemistry, materials science, biology, and medicine have of the focuses in the eld of nanomedicine.8–10 In general, the key advantages of nanodrug delivery are longer circulating half- College of Chemistry, Chemical Engineering and Materials Science, Collaborative lives, improved pharmacokinetics, selective intratumoral accu- Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, mulation, and lower systemic toxicity. Meanwhile, some other Shandong Normal University, Jinan 250014, P. R. China. E-mail: guangbo.wang@ emerging minimally invasive therapies, such as photothermal sdnu.edu.cn; [email protected] Qun Guan is currently a PhD Dr Guang-Bo Wang received his student. He received his Bache- Master's from the Dalian lor's in Chemistry from the University of Technology in 2014 University of Jinan (UJN) in and obtained his PhD in Chem- 2015. He received his Master's istry from Ghent University in in Organic Chemistry from 2018. Then, he moved back to Shandong Normal University China and joined Shandong under the guidance of Prof. Yu- Normal University at Prof. Yu- Bin Dong in 2019 and has Bin Dong's group in the same subsequently continued his PhD year. His current research research. His research focuses interest mainly focuses on the on MOF and COF nanomaterials rational design and preparation for cancer diagnosis and of advanced crystalline porous therapeutics. materials (e.g., MOFs and COFs) for related applications. 3656 | Nanoscale Adv.,2020,2,3656–3733 This journal is © The Royal Society of Chemistry 2020 View Article Online Review Nanoscale Advances therapy (PTT) and photodynamic therapy (PDT), have also through coordination bonds. The highly ordered structures of exhibited promising potential in oncotherapy due to their high MOFs allow precise control over their pore shapes and chemical selectivity, low side-effects, and negligible drug resistance.11–14 environments, thereby realizing controllable regulation of their Rapid developments in nanomaterials and nanotechnology properties.36 In the past decade, MOFs have been widely applied have provided a vast material reservoir for use in cancer nano- in the eld of oncology and have even entered the stage of medicine, which mainly include mesoporous silica,15 metal clinical trials.37–39 With the development of reticular chem- chalcogenides,16 upconversion materials,17 MXenes,18,19 carbon- istry,40 a new generation of crystalline porous materials, namely, based materials,20,21 semiconducting polymers,22,23 and covalent organic frameworks (COFs), emerged in 200541 and liposomes.24 have been booming in recent years.42 As a natural extension of The design, synthesis, and applications of advanced porous MOFs, COFs are composed of nonmetallic elements (e.g.,C, materials with specic structures at the micron- and nanoscales H, N, O, and B) connected by strong covalent bonds into two- have been a research hotspot in various scientic elds;25–30 dimensional (2D) or three-dimensional (3D) crystalline frame- further, the development of porous materials ranging from works with predictable and periodic structures.43,44 Due to the traditional inorganic materials (such as zeolites, silicas, and diversity of organic syntheses, COFs provide promising pros- activated carbons) to organic–inorganic hybrid porous mate- pects for materials design, enabling function- and application- rials (such as metal–organic cages (MOCs),31 coordination oriented material syntheses. Until now, COFs have been polymers (CPs),32 and metal–organic frameworks (MOFs)).33–35 widely used for separation and analysis,45–49 heterogeneous Among them, MOFs are crystalline materials formed by the self- catalysis,50–52 sensing,53 optoelectronics,54 energy and environ- assembly of organic ligands and metal ions (or clusters) mental science,55–59 and biomedicine.60,61 In recent years, COFs, particularly nanoscale COFs (NCOFs), have joined a huge candidate library of biomedical nano- materials because of their following unique features. (i) On Le-Le Zhou received her Bache- Creative Commons Attribution 3.0 Unported Licence. account of their modular structures, COFs can be easily deco- lor's in Applied Chemistry from rated with multiple functional compositions, enabling diverse the University of Jinan in 2015. biomedical applications, such as tumor targeting, uorescence She received her Master's in imaging, and cancer therapy. (ii) Due to their inherent porosity, Organic Chemistry from Shan- COF cavities allow the encapsulation of various guest mole- dong Normal University (SDNU) cules, thereby facilitating controlled drug release. (iii) Owing to under the supervision of Prof. Yu- their conjugated structures, the energy level structure of a COF Bin Dong in 2018. Then, she monomer is different in the framework. By tuning the topo- worked as a Lecturer at the logical structures and geometric parameters to optimize the This article is licensed under a School of Chemical and Biolog- directional energy and charge transport, COFs may have optical ical Engineering, Qilu Institute of properties that cannot be realized within the monomers, which Technology, from 2018 to 2020. offers additional and unexpected possibilities for imaging and Currently, she is a PhD candidate Open Access Article. Published on 16 July 2020. Downloaded 10/10/2021 9:30:22 AM. therapeutic applications of COFs. (iv) The metal-free nature of under the supervision of Prof. Yu-Bin Dong. Her research interests COFs prevents any potential biological toxicity caused by metal include advanced nanomaterials for preventing and treating elements.62 To sum up, we believe that COFs are becoming tumors. Wen-Yan Li received her Bache- Prof. Dr Yu-Bin Dong is the lor's in Chemistry from Shan- Chang Jiang Scholar of Chem- dong Normal University in 2017. istry at Shandong Normal Since 2017, she has been University (SDNU). He obtained working as a doctoral candidate his PhD from Nankai University under the guidance of Prof. Yu- (under Prof. Li-Cheng Song) in Bin Dong at Shandong Normal 1996. Then, he joined Prof. University. Her research focuses Andreas Mayr's group at the on MOF and COF composite University of Hong Kong and materials for cancer treatment. Prof. Hans-Conrad zur Loye's group at the University of South Carolina from 1996 to 2000, and he was promoted as a Full Professor at SDNU in 2000. He is the author of over 200 peer- reviewed publications. His current research interests mainly focus on MOF- and COF-based materials and their applications in catalysis, sensing, bioimaging, and cancer treatment. This journal is © The Royal Society of Chemistry 2020 Nanoscale Adv.,2020,2,3656–3733 | 3657 View Article Online Nanoscale Advances Review organic building blocks connected via covalent bonds.63 Until now, most of the reported COFs have been 2D structures. The structure of a 2D COF consists of 2D sheets held together by covalent bonds, which are then stacked together through non- covalent p–p interactions. For example, 2D monosheets