Nucleic Acid Nanotechnology in Acute Kidney Injury

Nucleic Acid Nanotechnology in Acute Kidney Injury: Comparison

Please note this is a comparison between Version 2 by Peter Tang and Version 1 by Yiwen Ying.

nucleic acid nanotechnology
AKI
aptamer
framework nucleic acids
diagnosis
targeted therapy
biomarkers

1. Introduction

Acute kidney injury (AKI) is a clinical syndrome characterized by an abrupted decline in renal function due to miscellaneous factors, such as rapid volume depletion, acute infection, nephrotoxic medicines and so on, leading to a retention of nitrogen wastes and creatinine accompanied by electrolyte disturbances and acid-base imbalance [1,2]^[1][2]. Accordingly, AKI occurs in more than 50% of patients in intensive care unit (ICU) while mortality reaches 10~20% even in non-ICU hospitalized patients suffering AKI, spawning huge significance to its early identification and medical intervention [3,4]^[3][4]. However, current clinical approaches are complicated with several drawbacks. For instance, serum creatinine, the mostly used index to evaluate renal status, is easily affected by individual differences, hindering its accuracy as a diagnostic method ^[5]. Other commonly utilized detection methods may also require much time as well as skillful techniques ^[6]. As for AKI therapies, mainly symptomatic treatment is provided without consistent standards or specific medicines ^[7]. Hence, given the fast progression and life threatening feature of AKI, it calls for more rapid and efficient diagnostic and therapeutic strategies ^[4].

Nucleic acids have no longer been limited to the definition of genetic information carrier. Originated from Dr. Seeman’s idea in the 1980s, nucleic acids have turned out to be unique but reliable bricks for biological nanomaterials realized by the predictable Watson-Crick base pairing rule and infinite combinations and permutations [8,9]^[8][9]. In the past decade, the concept of nucleic acid nanotechnology has further blossomed in the field of biomedical science, including smart drug delivery systems and molecular recognition tools [10,11]^[10][11]. Its advantages in disease diagnosis can be attributed to the precise recognition, tailored modifications and abundant amplification strategies while nucleic acid nanotechnology-based therapeutics benefit from advantages of structural programmability, spatial addressability and excellent biocompatibility [12,13]^[12][13]. Recently, an increasing number of research focus on the applications of nucleic acid nanotechnology in nephrological diseases as the inborn renal clearance endows kidneys with prominent biodistribution of certain DNA nanostructures over other organs, setting foundation for the kidney-targeting methods with nucleic acid nanotechnology ^[14] (Figure 1).

Figure 1. Schematic diagram of how nucleic acid nanotechnology plays a part in the diagnostic and therapeutic strategies of acute kidney injury (AKI). In AKI diagnostics, aptamers, DNA nanostructures as well as nucleic acid probes can be functionalized to detect AKI-related protein biomarkers, small molecules and nucleic acids. Meanwhile, in AKI therapeutics, oxidative stress, ferroptosis, immune responses and cellular apoptosis can be targeted with DNA tetrahedrons, DNA origamis and well-directed short interference RNAs (siRNAs). Created with BioRender.com (26 February 2022).

2. Diagnostics of AKI Based on Nucleic Acid Nanotechnology

Despite the fact that nucleic acid nanotechnology has been extensively investigated in cancer diagnosis, its research in AKI detection is still on the rise, among which aptamer may emerge as a robust tool for the disease diagnosis ^[10]. Aptamer, also known as chemical antibody, is a single stranded DNA or RNA (ssDNA/ssRNA) molecule which possesses high specificity as well as affinity towards multifarious ligands, from macromolecules such as proteins, to micro molecules such as peptides, amino acids, and metal ions [15,16,17]^[15][16][17]. These outstanding characteristics form the prerequisite for novel biosensing platforms while integration with new biomaterials magnifies the advantages of aptamers, boosting both sensitivity and specificity of in-time disease diagnosis, especially for AKI which urges earlier judgment and intervention ^[18] (Table 1).

Table 1.

A summary of extant nucleic acid nanotechnology-based diagnostics towards AKI-related biomarkers.

Diagnostic Targets		Type of Receptor	Type of Surface or Electrodes	Methods	Samples	LOD	Range of Detection	Refs
Proteins	NGAL	NGAL antibody and DNA aptamer	/	ELAA	Buffer and Human AKI urine	30.45 ng mL⁻¹	125~4000 ng mL⁻¹	^[19]
		FAM-labelled DNA aptamer	PDANS	Fluorescence detection and DNase I-aided amplification	HK-2 cells and Mice AKI urine	6.25 pg mL⁻¹	12.5~400 pg mL⁻¹	^[20]
		DNA aptamer	GNP-modified biochip	SWV	Buffer	0.07 pg mL⁻¹	0.1~10 pg mL⁻¹	^[21]
		Redox reporter-modified DNA aptamer	Gold electrodes	SWV	Artificial and Human urine	2 and 3.5 nM	Covers 2~32 nM	^[22]
		DNA aptamer	AgNP IDE	EIS	Buffer and Artificial urine	10 and 3 nM	3~30 and 3~300 nM	^[23]
		RNA aptamer	Microcantilever sensor	Differential interferometry	Buffer	96 ng mL⁻¹	Covers 100~3000 ng mL⁻¹	^[24]
	CysC	DNA-linked antibody pair	AuNP-functionalized Fe₃O₄ and G/mRub	ECL measurement and DNA strand displacement-mediated amplification	Buffer and Human serum	0.38 fg mL⁻¹	1.0 fg mL⁻¹~10 ng mL⁻¹	^[25]
		FAM-labelled DNA aptamer	GO	Fluorescence detection and DNase I-aided amplification	Buffer and Mice AKI urine	0.16 ng mL⁻¹	0.625~20 ng mL⁻¹	^[26]
		CysC antibody and DNA aptamer	/	Competitive ELASA	Buffer and Human serum	216.077 pg mL⁻¹	/	^[6]
		CysC antibody and DNA aptamer	/	Quantitative fluorescence LFA	Buffer and Human urine	0.023 μg mL⁻¹	0.023~32 μg mL⁻¹	^[27]
	RBP4	DNA aptamer	Gold chip	SPR	Artificial serum	1.58 µg mL⁻¹	/	^[28]
	Albumin	Cy5-labelled DNA aptamer	GO	Fluorescence detection	Human urine and human serum	0.05 µg mL⁻¹	0.1~14.0 µg mL⁻¹	^[29]
	Albumin	DNA aptamer	Magnetic beads	DPV aided with methylene blue solution	Artificial and Human urine	0.93~1.16 µg mL⁻¹ (pH-related)	10~400 µg mL⁻¹	^[30]
Small molecules	Urea	DNA aptamer	AuNP	Colorimetric detection	Milk sample	20 mM	20~150 mM	^[31]
Small molecules	Urea	DNA aptamer	CNTs/NH₂-GO	DPV	Buffer and Human urine	370 pM	1.0~30.0 nM and 100~2000 nM	^[32]
Nucleic acids	miR-21	DNA probes	Magnetic beads	ECL measurement and HCR-mediated amplification	Buffer and Human AKI urine	0.14 fM	1 fM~1 nM	^[33]
	miR-21	DNA probes	/	ECL measurement TMSD- and DNA NCs-aided amplification	Buffer and Cell lines	0.65 fM	1 fM~100 pM	^[34]
	miR-16-5p	DNA probes	Capped gold nanoslit	SPR	Human AKI urine	17 fM	Up to nanomolar	^[35]

Cys C, cystatin C; RBP4, retinol binding protein 4; LOD, limit of detection; ELAA, enzyme-linked aptamer analysis; FAM, 5-carboxyfluorescein; PDANS, polydopamine nanosphere; HK-2, human kidney 2 cells; GNP, graphene nanoplatelets; SWV, square wave voltammetry; AgNP, silver nanoparticle; IDE, interdigitated electrode; EIS, electrochemical impedance spectroscopy; AuNP, gold nanoparticle; G/mRub, monolayer rubrene functionalized graphene composite; ECL, electrochemiluminescence; GO, graphene oxide; ELASA, enzyme-linked aptamer sorbent assay; LFA, lateral flow assay; SPR, surface plasmon resonance; Cy5, cyanine 5; DPV, differential pulse voltammetry; CNT, carbon nanotubes; NH2-GO, amine-functionalized graphene oxide; HCR, hybridization chain reaction; TMSD, toehold-mediated strand displacement; DNA NCs, DNA nanoclews.

3. Therapeutic Approaches of AKI Based on Nucleic Acid Nanotechnology

Pathophysiology of AKI is rather complex, including extensive tubular oxidative stress, excessive release of inflammatory cytokines, activation of complement system, ferroptosis, necroptosis, cell cycle arrest and so on [88,89,90,91]^{[36][37][38][39]}. Albeit the springing up of various preclinical research of AKI therapeutics, they are still impeded by several factors, such as the poor targeting ability and the subsequent low efficiency, causing off-target effects in other organs and adverse drug reaction due to a higher administration dose to meet the expected efficacy [92,93]^[40][41]. Furthermore, the immunogenicity and biostability have also been a concern. Benefiting from the excellent biocompatibility and a preferential renal clearance, nucleic acid nanotechnology has been increasingly interrogated in the field of AKI treatment.

3.1. Therapeutics Targeting Oxidative Stress

Rhabdomyolysis (RM), which is usually due to severe burns or traumatic injuries and characterized by damage of skeletal muscle and outflow of cell contents, can induce AKI (RM-AKI) [94]^[42]. The leakage of uric acid and iron-containing hemoprotein myoglobin can be pathogenic, resulting in oxidative stress and inflammasome activation in renal tubules, including the formation of reactive oxygen species (ROS) [90,95]^[38][43]. Lin’s team demonstrated an antioxidative role of DTNs (average size ≈ 11.7 nm) in RM-AKI [96]^[44]. Researchers disclosed the ROS scavenging effect of DTN itself, which was consistent with previous studies showing DNA neutralization of oxidative substances [97]^[45]. What’s more, DTNs could transcriptionally upregulate nuclear factor E2 related factor 2/heme oxygenase-1 (NRF2/HO-1) axis, which was protective against oxidative stress, thus exerting further antioxidant effects [98]^[46]. On the other hand, DTNs also alleviated cell apoptosis through rescuing mitochondrial dysfunction and regulating mRNA level of apoptosis-related proteins B-cell lymphoma 2 (BCL2)/BCL-2-associated X protein (BAX).

In 2018, Jiang et al. ^[14] explored the antioxidative potential of DNA origami nanostructures (DONs) towards RM-AKI in vivo through PET imaging. Accordingly, DONs have risen as a successful implementation of DNA self-assembly, which are composed of an M13 phage-derived long ssDNA (scaffold), orchestrated by many short ssDNAs (staples), forming prescribed structures or patterns and realizing multiple functions, including addressable positioning of nanoparticles and targeted drug delivery [99,100,101]^[47][48][49]. In Jiang’s article, differently shaped DONs displayed preferential accumulation in kidney parenchyma over liver sequestration and were followed by whole-body clearance within 24 h, among which the rectangular DONs (Rec-DONs) seemed to accumulate the most (although not statistically significant). Rec-DONs (60 × 90 nm) could also pile up in renal tubules of experimental RM-AKI mice, yet with a longer excretion time, laying foundation for the retention-based treatment efficacy. A therapeutic dose (10 µg mouse⁻¹) of Rec-DONs could obviously ameliorate AKI with a robust ROS-scavenging effect, displaying a similar effect to high-dose N-acetylcysteine, a clinically used antioxidant. With a proved biostability, non-toxicity and low immunogenicity, Rec-DONs might play a more significant role not only as an active drug but also as a useful carrier in AKI therapies upon further modifications and optimization. Of note, their work also hinted that biodistribution and biodynamics of nanostructures could be partially determined by their well-designed shapes and sizes, given the clue that more condensed origami structures, such as Rec-DONs, displayed a much better renal-over-liver accumulation than ssDNAs or partially folded scaffold strand, providing innovative perspectives for future design of DNA-based nanotherapeutics.

Ischemia-reperfusion (I/R) is one of the most common causes of AKI, in which the mismatch between oxygen supply and waste metabolism mediates renal mitochondrial dysfunction, leading to ROS production and a subsequent series of deleterious responses including inflammation and apoptosis [88,102]^[36][50]. In 2021, Chen et al. [103]^[51] also employed Rec-DONs to mitigate I/R AKI. Based on their long retention time in kidneys (>12 h) as well as the timeline of pathophysiological progression in AKI, the team delicately introduced aptamers that could specifically block complement component 5a (C5a) to Rec-DONs, in which the ROS-sensitive DNA nanostructure itself contributed to antioxidative effects during the first 8 h while the lodged anti-C5a aptamers competitively bound C5a, thus suppressing further inflammatory responses 8 h after I/R AKI. Their nanodevice not only targeted double factors, but also realized a sequential and continuous treatment for AKI.

Keeping the above in view, these research disclosed a promising antioxidative effect of DNA nanostructures as well as its derivative devices.

3.2. Therapeutics Targeting Ferroptosis

Ferroptosis is a recently identified mode of regulated cell death dependent on accumulated reactive iron and lipid peroxidation [104,105]^[52][53]. It has also been reported to play a significant role in cisplatin-induced AKI (cis-AKI) and folic acid-induced AKI other than the commonly involved types of cellular death [106,107]^[54][55]. Wu’s group revealed DTNs (≈18.79 nm) possessed therapeutic potential against ferroptosis in cis-AKI, where it could rescue renal proximal tubular epithelial (HK-2) cells treated with ferroptosis-inducer in vitro through reducing lipid ROS as well as reversing the downregulation of glutathione peroxidase 4 (GPX4) in both transcription and translation level [108]^[56]. Similar restoration of GPX4 expression was also observed in cisplatin-treated HK-2 cells, further accompanied by apoptosis inhibition via reducing the cleavage of poly (ADP-ribose) polymerase. Their work was the first who revealed the anti-ferroptosis effect of DTNs in AKI, paving a way for more nanotherapeutics targeting this pathway. Notice that, transcription of GPX4 could be increased with NRF2 accordingly, and the study in Section 3.1 [96]^[44] happened to demonstrate an elevated mRNA level of NRF2 after DTN intervention in renal cells [96,109]^[44][57]. Whether the restoration of GPX4 expression in this research was due to DTN-mediated upregulation of NRF2 needs to be further investigated.

3.3. Therapeutics Targeting Immune Responses

Recently, Liu and Zheng’s team constructed a cytokine-based nanoraft targeting immune responses in I/R AKI [110]^[58]. 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]^[59]. The team then validated their Rec-DON-functionalized nanomachine could accumulate in kidney for up to 48 h. Compared with free IL-33 therapy, their nanorafts managed to reach a better therapeutic effect in I/R AKI mice models with a lesser dosage and a lower administration frequency, in which the long-term kidney-localized release of IL-33 successfully expanded type 2 innate lymphoid cells and regulatory T cells, ameliorating the injured kidney. Of note, their invention could also accumulate in liver promptly after intravenous injection of nanorafts. Although no obvious hepatic side effects found in this study, further improvement was still expected to realize a more precise renal targeted delivery probably through some peptide modifications. Nevertheless, their precise design efficiently avoided the main limitations of conventional cytokine immunotherapy where free IL-33 had a rather short half-life and non-specificity to kidney-resident immune cells [112]^[60].

3.4. Therapeutics Targeting p53-Related Cellular Apoptosis

p53, a pivotal tumor-suppressor protein, has been extensively reported for regulating cellular apoptosis [113]^[61]. It is demonstrated in AKI that proximal tubular p53 can be pathogenic by inducing several vital genes related to cell death regulation [114]^[62]. On the other hand, short interference RNA (siRNA) is double-stranded RNA molecule composed of 21~25 nucleotides which can induce degradation of target RNAs in a sequence-specific manner, thus frequently functionalized in muting p53 gene as a nanoscale nucleic acid tool [115]^[63]. Experiments have shown a beneficial effect of p53-targeted siRNAs towards ischemia and cisplatin-induced AKI, presenting a dose and time-dependent attenuation of apoptotic signaling [116]^[64]. However, the application of these p53-aiming siRNAs is still complicated with poor pharmacokinetics, susceptibility to nuclease degradation and off-target effects due to non-specific delivery, calling for more possible vehicle nanoplatforms and appropriate modifications aiming at more well-directed efficacy and fewer side effects in AKI treatment [92]^[40].

Recently, Tang and colleagues electrostatically loaded p53 siRNA upon their previously explored chemical nanocarrier, polymeric C-X-C chemokine receptor 4 (CXCR4) antagonist (PCX), which was a linear polymer composed of phenylene-cyclam derivative and hexamethylene-bis-acrylamide and was about 127 nm in size [117,118]^[65][66]. Notice that, PCX not only blocked inflammation-related membranous CXCR4 from receiving upstream signals and transducing pathogenic responses, but also mediated endocytosis of the PCX/siRNA polyplexes upon membranous CXCR4-binding in injured tubular cells. With dual-functionality and durable renal retention in AKI, the nanoparticles favorably accumulated in injured kidney tubules and robustly ameliorated apoptotic events with a reduced p53 siRNA dose of 0.6 mg/kg compared to naked ones. Alidori et al. [119]^[67] exploited ammonium-functionalized carbon nanotubes (fCNTs) (≈300 nm) in the dual-delivery of siRNAs aiming at p53 and meprin-1β, another key factor involved in AKI procedure, to proximal tubular cells specifically [120]^[68]. This nanocomplex was proved in murine cis-AKI models to prophylactically attenuate AKI with a cumulative siRNA dose of 0.4 mg/kg; meanwhile, its pharmacodynamic profile was evaluated in primates for the first time, which was consistent with the results in mice and might facilitate its clinical transformation.

DNA nanostructure can also be employed as a cytosolic delivery tool for the anti-apoptotic oligonucleotides since the cargo siRNAs can easily satisfy the principle of base-pairing with the carrier. Thai et al. [121]^[69] prepared L-sTD, a mirror DNA tetrahedron with 10 bp on each side and sugar backbone modifications, demonstrated with a kidney-preferred distribution in vivo. Meanwhile, the small size (≈6 nm) of L-sTD allowed itself to filter through glomerular base membrane freely and undergo megalin-mediated endocytosis by renal tubular cells. The team then applied siRNA targeting p53 (siP53) to L-sTDs forming siP53@L-sTD via hybridization of two designed linker DNA strands and eventually proved its anti-apoptotic therapeutic effects for AKI in vivo through downregulating p53 transcriptionally. Further experiments elucidated siP53@L-sTD outperformed naked siP53 mainly due to its successful escape from endosome entrapment, which was mediated by interaction between L-sTds and lipids at lowered pH within endosomes, resulting in membrane destabilization. This research managed to solve the main challenges of siRNAs by lowering the dosage (from 5 mg/kg to 0.25 mg/kg per injection) with a higher cellular uptake efficiency and minimizing off-target effects with kidney-specific delivery.

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