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

• 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. Compared with naked CpG-MOF, isMOFs exhibited 83-fold up-regulation in stimulated secretion of cytokines. We thus expect this isMOF design with soluble CaP exoskeleton and an embedded sequential "protect-release" program provides a highly generic approach for intracellular delivery of therapeutic nucleic acids.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Andra medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Other Basic Medicine (hsv//eng)

Nyckelord

Biocompatibility

Calcium compounds

Crystalline materials

Medical applications

Nanoparticles

Nucleic acids

Oligonucleotides

Organometallics

Acidic environment

Biomedical applications

Intracellular delivery

Metal organic framework

Metalorganic frameworks (MOFs)

Spatiotemporal control

Surface functionalities

Toll-like receptors

DNA

calcium phosphate

cytosine

guanosine

immunostimulating agent

interleukin 6

nanoparticle

oligonucleotide

phosphate

toll like receptor 9

tumor necrosis factor

zirconium

acidity

Article

carbon nuclear magnetic resonance

chemical binding

conformation

controlled study

cytokine release

cytotoxicity

exoskeleton

fluorescence spectroscopy

immunostimulation

immunotherapy

interactions with DNA

RAW 264.7 cell line

transmission electron microscopy

upregulation

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)