Organelle-Specific Triggered Release of Immunostimulatory Oligonucleotides from Intrinsically Coordinated DNA–Metal–Organic Frameworks with Soluble Exoskeleton

作者：Zejun Wang, Yao Fu, Zhengzhong Kang, Xiaoguo Liu, Nan Chen, Qi Wang, Yaoquan Tu, Lihua Wang, Shiping Song, Daishun Ling, Haiyun Song, Xueqian Kong, Chunhai Fan · 发表于：Journal of the American Chemical Society · 年份：2017 · DOI：10.1021/jacs.7b07895 · 被引用次数：258 · 研究领域：RNA Interference and Gene Delivery、Metal-Organic Frameworks: Synthesis and Applications、Advanced biosensing and bioanalysis techniques

DNA has proven of high utility to modulate the surface functionality of metal-organic frameworks (MOFs) for various biomedical applications. Nevertheless, current methods for preparing DNA-MOF nanoparticles rely on either inefficient covalent conjugation or specific modification of oligonucleotides. In this work, we report that unmodified oligonucleotides can be loaded on MOFs with high density (∼2500 strands/particle) via intrinsic, multivalent coordination between DNA backbone phosphate and unsaturated zirconium sites on MOFs. More significantly, surface-bound DNA can be efficiently released in either bulk solution or specific organelles in live cells when free phosphate ions are present. As a proof-of-concept for using this novel type of DNA-MOFs in immunotherapy, we prepared a construct of immunostimulatory DNA-MOFs (isMOFs) by intrinsically coordinating cytosine-phosphate-guanosine (CpG) oligonucleotides on biocompatible zirconium MOF nanoparticles, which was further armed by a protection shell of calcium phosphate (CaP) exoskeleton. We demonstrated that isMOFs exhibited high cellular uptake, organelle specificity, and spatiotemporal control of Toll-like receptors (TLR)-triggered immune responses. When isMOF reached endolysosomes via microtubule-mediated trafficking, the CaP exoskeleton dissolved in the acidic environment and in situ generated free phosphate ions. As a result, CpG was released from isMOFs and stimulated potent immunostimulation in living macrophage cells...