A novel metal-organic framework encapsulated iridium oxide nanozyme enhanced antisense oligonucleotide combo for osteoarthritis synergistic therapy  

作　　者：Shuqi Wu Fang Nan Kewen Zhang Wan Hao Di Shi Yang Li Wei Deng Nur Jarhen Kaixuan Li Yunyun Xiao Jun Li Xiao Lin 

机构地区：[1]School of Life Sciences,Key Laboratory of Space Bioscience&Biotechnology,Northwestern Polytechnical University,Xi’an,China [2]School of Life Sciences,Lab for Bone Metabolism,Xi’an Key Laboratory of Special Medicine and Health Engineering,Research Center for Special Medicine and Health Systems Engineering,NPU-UAB Joint Laboratory for Bone Metabolism,Xi’an,China [3]Institute of Chemistry and Biochemistry,Freie Universität Berlin,Berlin,Germany [4]Department of Joint Surgery,Honghui Hospital,Xi’an Jiaotong University,Xi’an,China [5]Research&Development Institute of Northwestern Polytechnical University in Shenzhen,Shenzhen,China

出　　处：《Aggregate》2024年第6期352-366,共15页聚集体(英文)

基　　金：Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2023A1515030047;Natural Science Basic Research Plan in Shaanxi Province of China,Grant/Award Numbers:2024JC-YBMS-605,2024JC-YBMS-086;National Natural Science Foundation of China,Grant/Award Numbers:22367015,81672172;National Undergraduate Training Programs for Innovation and Entrepreneurship,Grant/Award Numbers:S202310699405,S202210699549。

摘　　要：Osteoarthritis(OA)is associated with metabolic imbalance of articular cartilage and an increase of intracellular reactive oxygen species(ROS).Synergistic therapy based on the codelivery of ROS scavengers and antisense oligonucleotides(ASO)into chondrocytes has the potential to effectively treat OA.Here,we developed a novel biocompatible metal-organic framework(MOF)-encapsulated nanozyme/ASO delivery platform(miR/IrO_(2)@ZIF-8)for OA treatment.IrO_(2) nanoparticles with the catalytic activities of superoxide dismutase/catalase were synthesized using a hydrothermal method,resulting in excellent ROS scavenging performance.IrO_(2) was further loaded into zeolitic imidazolate framework-8(ZIF-8)to maintain its catalytic efficacy and regulate its size,surface charge,and biocompatibility to enhance the therapeutic effect of the platform.As an effective ASO delivery carrier,the synthesized IrO_(2)@ZIF-8 exhibited high antagomiR-181a loading and lysosomal escape capacity,enabling it to rebalance cartilage metabolism.In vitro experiments showed that miR/IrO_(2)@ZIF-8 could restore ROS levels,mitochondrial membrane potential,and lipid peroxidation in chondrocytes.At the same time,the expression levels of proinflammatory markers(IL-1β,IL-6,and COX-2)as well as the extracellular matrix degrading enzymes(ADAMTS-5 and MMP13)were downregulated,indicating effective antioxidant,anti-inflammatory,and anticartilage degradation effects.Notably,miR/IrO_(2)@ZIF-8 was able to deliver IrO_(2) nanoparticles and antagomiR-181a to the cartilage tissue at a depth of up to 1.5 mm,thus solving the problems of poor permeability and difficult retention of drugs in cartilage tissue.This further improves the synergistic therapeutic effect on OA by inhibiting cartilage degradation.The combination of MOF-encapsulated IrO_(2) nanozymes with antagomiR-181a has an excellent therapeutic effect on OA,offering a promising translational medicine paradigm.

关 键 词：antisense oligonucleotides cartilage metabolism drug delivery IrO_(2)nanozyme osteoarthritis treatment reactive oxygen species scavenging 2’ 7’-dichlorodihydrofluorescein diacetate 

分 类 号：R73[医药卫生—肿瘤]