A DNA Nanoraft-Based Cytokine Delivery Platform for Alleviation of Acute Kidney Injury

Abstract

Cytokine immunotherapy represents an attractive strategy to stimulate robust immune responses for renal injury repair in ischemic acute kidney injury (AKI). However, its clinical application is hindered by its nonspecificity to kidney, short circulation half-life, and severe side effects. An ideal cytokine immunotherapy for AKI requires preferential delivery of cytokines with accurate dosage to the kidney and sustained-release of cytokines to stimulate the immune responses. Herein, we developed a DNA nanoraft cytokine by precisely arranging interleukin-33 (IL-33) nanoarray on rectangle DNA origami, through which IL-33 can be preferentially delivered to the kidney for alleviation of AKI. A nanoraft carrying precisely quantified IL-33 predominantly accumulated in the kidney for up to 48 h. Long-term sustained-release of IL-33 from nanoraft induced rapid expansion of type 2 innate lymphoid cells (ILC 2s) and regulatory T cells (Tregs) and achieved better treatment efficiency compared to free IL-33 treatment. Thus, our study demonstrates that a nanoraft can serve as a structurally well-defined delivery platform for cytokine immunotherapy in ischemic AKI and other renal diseases.

Salting-Out of DNA Origami Nanostructures by Ammonium Sulfate

“…DNA origami nanostructures, first introduced in 2006 [ 1 ], have developed into widely used, highly versatile tools for addressing important problems and challenges in biophysics [ 2 , 3 ], biomedicine [ 4 , 5 ], molecular [ 6 , 7 ], structural [ 8 , 9 ], and chemical biology [ 10 , 11 ], sensing [ 12 , 13 ], microscopy [ 14 , 15 ], and many other fields of fundamental and applied research. Although these applications have benefited from the numerous advantages that make DNA origami nanostructures superior to other, more conventional nanostructures, such as high biocompatibility [ 16 , 17 ], high stability in comparatively harsh environments [ 18 , 19 ], and the unprecedented possibility to arrange molecular species with sub-nanometer accuracy [ 11 , 20 ], there are still several challenges that need to be overcome for this technology to enter real-world applications.…”

Nanodrugs alleviate acute kidney injury: Manipulate RONS at kidney

“…Recently, Li et al developed DNA nanocrafts for AKI anti-inflammatory treatment ( Fig. 16 B) [ 224 ]. DNA nanocrafts were constructed with two-dimensional DNA origami as carriers, single-stranded DNA as joints, and immunomodulator interleukin-33 (IL-33) as cargos.…”

“…Adapted with permission from Ref. [ 224 ], copyright 2021. (G) Schematic illustration of renoprotective effect of MSC-EVs for AKI treatment.…”

Nucleic Acid Nanotechnology for Diagnostics and Therapeutics in Acute Kidney Injury

“…Recently, Liu and Zheng’s team constructed a cytokine-based nanoraft targeting immune responses in I/R AKI [ 110 ] ( Figure 5 b). They programmed 42 capture strands rationally on the surface of Rec-DONs, followed by hybridization with DNA-modified interleukin-33 (IL-33), a renoprotective cytokine, thus realizing a precise and quantitative nanoassembly capable of releasing cytokine cargoes sustainably [ 111 ].…”

“…Copyright © 2022, American Chemical Society; ( b ) Sketch map of DON-based nanorafts rationally assembled with interleukin-33 and how the designed nanomachines function in immune-targeted AKI therapy. Adapted with permission from [ 110 ]. Copyright © 2022, American Chemical Society; ( c ) Schematic illustration of the conformation and noncovalent bonding between a fibrillar carbon nanotube and therapeutic short interference RNAs (siRNAs), realizing kidney-targeted delivery and AKI alleviation.…”