DNA origami nanostructures can exhibit preferential renal uptake and alleviate acute kidney injury

Abstract

Patients with acute kidney injury (AKI) frequently require kidney transplantation and supportive therapies, such as rehydration and dialysis. Here, we show that radiolabelled DNA origami nanostructures (DONs) with rectangular, triangular and tubular shapes accumulate preferentially in the kidneys of healthy mice and mice with rhabdomyolysis-induced AKI, and that rectangular DONs have renal-protective properties, with efficacy similar to the antioxidant N-acetylcysteine—a clinically used drug that ameliorates contrast-induced AKI and protects kidney function from nephrotoxic agents. We evaluated the biodistribution of DONs non-invasively via positron emission tomography, and the efficacy of rectangular DONs in the treatment of AKI via dynamic positron emission tomography imaging with 68Ga-EDTA, blood tests and kidney tissue staining. DNA-based nanostructures could become a source of therapeutic agents for the treatment of AKI and other renal diseases.

Real‐Time Observation of Superstructure‐Dependent DNA Origami Digestion by DNase I Using High‐Speed Atomic Force Microscopy

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GuidoG rundmeier, [a] AdrianK eller,* [a] andV eikkoL inko* [a, b, c] DNA nanostructures have emerged as intriguing tools for numerous biomedical applications. [11][12][13][14] For therapeutic in vivo applications, the DON vehicles should preferably be compatible with the immunes ystem, resistant to nucleases, have as ufficiently long circulation half-life, and be able to maintain their shape at the ionic strengths of the biological fluids. A particularly important issue for medicala pplications is their interaction with proteins such as endonucleases, which may degrade the well-defined nanoscale shapes.H erein, fundamental insights into this interaction are provided by monitoring DNase Id igestion of four structurally distinct DNA origami nanostructures (DONs) in real time and at as ingle-structure level by using high-speed atomic force microscopy.T he effect of the solid-liquidi nterface on DON digestioni sa lso assessed by comparison with experiments in bulk solution.

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“…[8,15,[19][20][21] Therefore, significant efforts have been madei nto coating ands tabilizing DONs under biologically relevant conditions. [11][12][13][14] According to the selected HS-AFMf ramess hown in Figure 2, the DONs adsorbed on the mica surface are not digested homogeneously by DNase I( control samples, i.e.,s amples without DNase I, are presented in Figures S1, S3, S5,S7, S9, and S11 in the Supporting Information). DNase Ii sw idely present in serum and varioust issues,w hich makes it one of the most relevantt hreatst ot he stability of DONs in vivo.…”

“…Previously,D ON cleavage by endonucleases was studied by employing ratherl ong timescales. [11][12][13][14] According to the selected HS-AFMf ramess hown in Figure 2, the DONs adsorbed on the mica surface are not digested homogeneously by DNase I( control samples, i.e.,s amples without DNase I, are presented in Figures S1, S3, S5,S7, S9, and S11 in the Supporting Information). Moreover,t hese experiments could neither reveals patial variations of DNase Is usceptibility within as ingle DON, nor facilitate parallel comparison of different structures under the same conditions.…”

“…[2][3][4][5] In recenty ears, programmable DNA origami nanostructures (DONs) [6][7][8][9][10] have been considered promising candidates for the development of tailored and multifunctional drug-delivery vehicles. [11][12][13][14] For therapeutic in vivo applications, the DON vehicles should preferably be compatible with the immunes ystem, resistant to nucleases, have as ufficiently long circulation half-life, and be able to maintain their shape at the ionic strengths of the biological fluids. [15] However,c oncerns have been raised regarding the stabilityo fD ONs and their performance in biological media.…”

“…[8,16] Therefore, thesea pproaches can only resolve the time points at which the whole or most of the nanostructure has been digested. [11][12][13][14] According to the selected HS-AFMf ramess hown in Figure 2, the DONs adsorbed on the mica surface are not digested homogeneously by DNase I( control samples, i.e.,s amples without DNase I, are presented in Figures S1, S3, S5,S7, S9, and S11 in the Supporting Information). Herein, we thus employ high-speed atomicf orce microscopy (HS-AFM) [26] to study the degradation of four well-established and structurally distinct 2D DON designs [6,27,28] (see Figure1 and the Supporting Information) under DNase Ia ttack at the single-structure level.…”