Glucose-Responsive Metal-Organic- Framework Nanoparticles Act as “Smart” Sense-and-Treat Carriers Wei-Hai Chen, † Guo-Feng Luo, † Margarita Va ́ zquez-Gonza ́ lez, † Re ́ mi Cazelles, † Yang Sung Sohn, ‡ Rachel Nechushtai, ‡ Yossi Mandel, § and Itamar Willner* ,† † Institute of Chemistry, Center for Nanoscience and Nanotechnology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel ‡ Institute of Life Science, The Hebrew University of Jerusalem, Jerusalem 91904, Israel § School of Optometry and Vision Science, Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel *S Supporting Information ABSTRACT: Zeolitic Zn 2+ -imidazolate cross-linked frame- work nanoparticles, ZIF-8 NMOFs, are used as “smart” glucose-responsive carriers for the controlled release of drugs. The ZIF-8 NMOFs are loaded with the respective drug and glucose oxidase (GOx), and the GOx-mediated aerobic oxidation of glucose yields gluconic acid and H 2 O 2 . The acidification of the NMOFs’ microenvironment leads to the degradation of the nanoparticles and the release of the loaded drugs. In one sense-and-treat system, GOx and insulin are loaded in the NMOFs. In the presence of glucose, the nanoparticles are unlocked, resulting in the release of insulin. The release of insulin is controlled by the concentration of glucose. In the second sense-and-treat system, the NMOFs are loaded with the antivascular endothelial growth factor aptamer (VEGF aptamer) and GOx. In the presence of glucose, the ZIF-8 NMOFs are degraded, leading to the release of the VEGF aptamer, which acts as a potential inhibitor of the angiogenetic regeneration of blood vessels by VEGF. As calcination of the VEGF-generated blood vessels leads to blindness of diabetic patients, the functional NMOFs might act as “smart” materials for the treatment of macular diseases. The potential cytotoxicity of the NMOFs originated from the GOx-generated H 2 O 2 is resolved by the co-immobilization of the H 2 O 2 -scavanger catalase in the NMOFs. KEYWORDS: aptamer, insulin, VEGF, nanomedicine, diabetes, macular diseases M etal-organic frameworks (MOFs) represent a broad class of porous materials that have attracted substantial research interest in recent years. 1-3 Different applications of MOFs include their use as porous matrices for the storage of gases, 4,5 carriers of particles for catalysis, 6,7 functionalization of MOFs with metal-ion/ligand complexes for catalysis, 8,9 the use of MOFs for sensing, 10-12 and their application for improving fuel cell performance. 13-15 Special efforts are directed to the use of MOFs as drug delivery vehicles and controlled release systems. 16-19 Different internal and external triggers have been used to release drugs entrapped in the MOF matrices, and these include pH, 20,21 temper- ature, 22 light, 23 reactive oxygen species (ROS), 24,25 and chemical agents. 26,27 Additional efforts are focused on the miniaturization of the MOFs into nanoparticle configurations, NMOFs. Besides the higher surface area and increased loading capacities per unit of weight of nanoparticles, their enhanced suspendability may improve intravenous invasive treatment with minimal clotting or arterial deposition phenomena. In this context, nucleic acid-modified metal-organic framework nanoparticles provide a promising stimuli-responsive platform for drug delivery and controlled release. Different nucleic acid structures were used to gate the controlled release of drug- loaded NMOFs, and different triggers such as pH, 28 aptamer- ligand complexes, 29,30 or DNAzymes 31 were used to unlock the NMOFs and release the drugs. One interesting biomaterial- NMOF hybrid system includes the encapsulation of the biomaterials in the NMOF structure within the process of formation of the NMOFs (one-pot synthesis). In this system, the biomaterials are coated by nanodomains of the NMOFs, resulting in cross-linked NMOF-biomaterial matrices. Differ- ent enzymes were encapsulated in NMOF matrices, and their Received: May 6, 2018 Accepted: July 3, 2018 Published: July 3, 2018 Article www.acsnano.org Cite This: ACS Nano 2018, 12, 7538-7545 © 2018 American Chemical Society 7538 DOI: 10.1021/acsnano.8b03417 ACS Nano 2018, 12, 7538-7545 Downloaded via BAR-ILAN UNIV on April 18, 2019 at 11:05:56 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.