DNA-Based Fluorescent Nanoprobe for Cancer Cell Membrane Imaging: Comparison
Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Chunmei Li.

As an important barrier between the cytoplasm and the microenvironment of the cell, the cell membrane is essential for the maintenance of normal cellular physiological activities. An abnormal cell membrane is a crucial symbol of body dysfunction and the occurrence of variant diseases; therefore, the visualization and monitoring of biomolecules associated with cell membranes and disease markers are of utmost importance in revealing the biological functions of cell membranes. Due to their biocompatibility, programmability, and modifiability, DNA nanomaterials have become increasingly popular in cell fluorescence imaging in recent years. In addition, DNA nanomaterials can be combined with the cell membrane in a specific manner to enable the real-time imaging of signal molecules on the cell membrane, allowing for the real-time monitoring of disease occurrence and progression.

  • DNA nanomaterials
  • cell membrane
  • fluorescence imaging

1. Introduction

The cell membrane is a semi-permeable membrane that acts as a natural barrier to prevent extracellular substances from freely entering cells, exhibiting a high selectivity, permeability, and fluidity [1,2,3][1][2][3]. Lipids and proteins are the primary components of the cell membrane. Lipid bilayers can self-assemble from membrane-forming lipids containing a hydrophilic head and two hydrophobic alkyl tails [4]. Consequently, the cell membrane functions as a barrier and gatekeeper to control the transport of information and substances within the cell. In addition, it plays a crucial role in protecting cells from extracellular influences, maintaining intracellular homeostasis, and regulating cell functions and behaviors [5,6][5][6].
Currently, X-ray tomography [7], magnetic resonance imaging [8], and ultrasound [9] have been widely applied to the study of disease development, but they cannot achieve the real-time monitoring of multiple molecules and physiological parameters in cells, preventing the timely acquisition of pertinent information such as disease progression [10]. However, some other imaging techniques can overcome the aforementioned drawbacks, such as biological imaging technology, which provides a more direct method of revealing multidimensional information from biomolecules and cells to organs and living individuals [11]. Cellular fluorescence imaging is significant for biosensing and early disease diagnosis owing to the following characteristics. Firstly, it has the advantages of visual biodistribution, real-time information feedback, and ease of operation [12]. Secondly, fluorescence imaging enables the simultaneous detection of multiple targets and the real-time imaging of cell-specific molecular targets, pathways, and physiology, enabling early accurate diagnosis and process monitoring of diseases [13,14][13][14].
Nucleic acids, which include DNA and RNA, are a type of classic biological macromolecule widely used for storing and transmitting genetic information. DNA is the carrier and transmitter of genetic information in all living systems, consisting of four different deoxynucleotide monomers, as is common knowledge. Each monomer consists of a phosphate group, deoxyribose, and one of four nitrogenous nucleobases, while the nucleobases include thymine (T), adenine (A), guanine (G), and cytosine (C) [17,18][15][16]. Watson and Crick reported the double helix structure of DNA for the first time in 1953, leading to extensive research on DNA structure [19][17]. DNA, the traditional genetic molecule, has attracted a great deal of interest due to its exceptional sequence programmability, high molecular recognition accuracy, and numerous biological functions. Due to their biocompatibility, simple synthesis, ease of modification and functionalization, and modular structure, nucleic acid probes, particularly DNA probes, have been widely used over the past few decades. In addition, they can be combined with various signal amplification techniques to achieve additional functions [20,21,22][18][19][20]. According to the spatial dimension of nanostructures, the DNA nanomaterials commonly used in current research are mainly categorized into the typical assembling strategies of one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) nanostructures [21][19]. DNA-based nanomaterials and functional DNA sequences (Aptamer, DNAzyme, i-motif, G-quadruplex, etc.) endow DNA nanostructures with functions such as targeting, stimulating responses, and regulating life activities, which demonstrate unique advantages in disease diagnosis and cancer therapy [23,24][21][22]. The fluorescent labeling of DNA is a common technique used for many applications in bioanalysis and imaging. Environmentally sensitive fluorophores can sense the interaction of DNA with other (biological) molecules by altering some measurable property of the fluorescence (the intensity, wavelength, or lifetime) [16][23].

2. Application of Cell Membrane Imaging

2.1. Monitoring Imaging Triggered by the Tumor Cell Microenvironment

The tumor microenvironment (TME) is a physical and biochemical system that plays a significant role in the occurrence, development, metastasis, and drug resistance of tumors [25][24]. In general, the tumor microenvironment’s physiological state is distinct from that of normal tissue. Tumor tissue can be distinguished from normal tissue according to a number of physiological characteristics, including the overexpression of ATP, an acidic pH, hypoxia, a high level of reactive oxygen species (ROS), and the overexpression of enzymes. Consequently, these characteristics have become increasingly desirable as diagnostic and therapeutic targets [26,27][25][26].

2.1.1. ATP

Adenosine triphosphate (ATP) is a fundamental biomolecule involved in numerous biochemical synthesis and metabolic processes. For a deeper understanding of the related cellular processes, it is crucial to examine the distribution of, and changes in, ATP outside the cell [28][27]. Utilizing DNA tweezers and cleavage aptamers, Zhong et al. [30][28] proposed a ratiometric DNA nanoswitch (Figure 1A). The nanoswitch consists of three uniquely designed ssDNA chains that are attached to the cell membrane via cholesterol. First, the DNA tweezers are in the open state, causing the fluorescent groups to separate and produce a low fluorescence resonance energy transfer (FRET) ratio. FRET is a mechanism that describes the transfer of energy between a photosensitive chromophore donor and an acceptor, and it is widely used in biochemistry and other areas [31][29].  ATP imaging analysis alone is typically insufficient for sensitive analysis, so researchers frequently employ signal amplification for more sensitive ATP imaging. Catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR) are two of the most widely used signal amplification strategies. The CHA is a reaction in which hairpin DNA can be activated by specific nucleic acid sequences and automatically forms a stable double-stranded body via thermodynamic entropy gain [32][30]. The HCR reaction requires the involvement of both hairpin DNAs, and in the presence of a target, one of the hairpin DNAs can be opened, which, in turn, triggers the opening of the other hairpin DNA to trigger the creation of the HCR, generating a long double-stranded tandem of DNA [33][31]. Wang et al. [34][32] proposed the signal amplification strategy of extracellular ATP-activated HCR amplification, which enables accurate and sensitive tumor cell detection. In complex biological matrices, this method has promising application potential. In addition, by altering the sequence of the corresponding aptamer, this method can be used to detect various types of tumor cells (Figure 1B). 
Figure 1. ATP imaging of the cell membrane. (A) Mechanism of the cell-surface anchored ratiometric DNA nanoswitch for the imaging of extracellular ATP [30][28]. The Apt-trigger probe consisted of two components: a ZYsls aptamer for specific binding to SMMC-7721 cells and a trigger sequence for initiating the HCR assembly. (B) (a) Schematic illustration of the extracellular ATP-activated hybridization chain reaction for cancer cell detection. (b) Flow cytometry assays and confocal fluorescence imaging of SMMC-7721 cells incubated with Apt-trigger/H1-ATP aptamer/H2 with or without the addition of ATP [34][32].

2.1.2. pH

In addition to the overexpression of ATP, extracellular pH (pHe) is a crucial microenvironmental factor in the development of tumors in the tumor microenvironment. The adjustment of pH value is essential for the maintenance of equilibrium in organisms. Several pathologies, such as ischemia, renal insufficiency, inflammation, and chronic lung disease, are typically associated with local pH fluctuations. Extracellular acidosis is becoming a universal indicator in the clinical diagnosis of tumors. To effectively distinguish normal cells from cancer cells, TME imaging must be sensitive. Nie et al. [38][33] designed a DNA tweezer composed of an i-motif to dynamically monitor pH changes in the cell microenvironment (Figure 2A). Double-stranded DNA can be hydrolyzed; it is not a suitable candidate for sensor functions in biological media. In contrast, framework nucleic acids have an excellent resistance to enzymatic hydrolysis and are widely employed in numerous sensors [41,42][34][35]. Yuan et al. [43][36] designed a programmable pH sensor that employs the tetrahedral DNA framework (TDF) structure as the skeleton and the DNA i-motif structure as the proton recognition probe (Figure 2B).
Figure 2. Acidic pH imaging of the tumor microenvironment. (A) Construction and principle of the pH-sensitive DNA tweezer [38][33]. The green ball is Rhodamine Green and the red ball is Rhodamine Red. DNA tweezer was anchored to the cell membrane by cholesterol. (B) The strategy to engineer programmable i-motif-TDF pH sensors [43][36].

2.1.3. Metal Ions

Some metal ions, such as sodium (Na+) and potassium (K+), play important roles in life processes, while ATP and pH have a wide variety of applications outside of cell surface imaging [48,49][37][38]. Cell surface K+ channels are assembled in the endoplasmic reticulum (ER) and transported through organelles to the plasma membrane [50][39]. In the process of rapid division, tumor cells release up to 50 mM of K+ into the extracellular space, thereby inhibiting the Akt-mTOR pathway and the activity of T-cell effector molecules, thus affecting their killing effect on T-cells, which causes cancer cells to escape the immune system and proliferate uncontrollably [51,52][40][41]. Extracellular potassium ions and ATP are found to be maintained at extremely high extracellular concentrations in the TME and are biomarkers for early cancer detection and tumor localization. DNA tetrahedral nanostructures are a typical class of DNA backbone nucleic acids with excellent mechanical rigidity, biocompatibility, and other advantages that have numerous potential applications in biology, biomedicine, and other fields.

2.2. Imaging of Cell Membrane Receptors

Receptors are a class of protein molecules that serve as subcellular cell surfaces or intracellular components. Receptors on the cell membrane play important roles in a variety of physiological and pathological processes and have become therapeutic targets for a large number of drugs [57,58][42][43]. G-protein-coupled receptors (GPCRs) and enzyme-linked receptors (especially RTKs) are the two largest known receptors among the thousands of known cell surface receptors in eukaryotes, and they also represent one of the hottest topics in the field of life science [59][44]. Recognizing extracellular stimuli and transducing cell signal pathways, cell surface receptors regulate fundamental cell behaviors, such as proliferation, migration, and differentiation [60][45]. Numerous membrane receptors, such as MUC1 [61][46], nucleolin [57][42], EGFR [62][47], epithelial cell adhesion molecules [63][48], etc., have been considered tumor markers and used for the specific imaging of cancer cells up to this point. The majority of these receptors are RTKs and participate in numerous intracellular signaling pathways associated with the growth and proliferation of cancer cells [64][49]. Ingeniously, Wang et al. [69][50] designed an i-motif with a hairpin as an acid response element and paired it with a tumor-targeting nucleic acid aptamer for the bispecific imaging and in situ drug release of tumor cells, dubbing it the “molecular doctor” (pH-Apt-MD) (Figure 4B). It uses the binding of, and structural changes in, nucleic acid aptamers to the i-motif, the dissociation of pH-Apt-MD, and the stimulation of FRET signaling between AF488 and Cy3 to achieve in situ drug release. The integration of tumor diagnosis and treatment is a major direction of development for cancer treatment at present. As a method of diagnosing tumors, the imaging of receptors on cell membranes has been widely reported, but there may be false positives. In contrast, multiple or distinct tumor markers in living cells are crucial for obtaining precise and multidimensional information regarding tumor cell types and tumor progression. Consequently, using receptors on the cell membrane as logical input signals can prevent false-positive results and enable the rapid and sensitive transmembrane sequential imaging of multilayer biomarkers that precisely distinguish tumor cell types.

2.3. Imaging of Other Molecules

A complex mixture of lipids, proteins, and other components composes the cell membrane. Some lipids and proteins interact preferentially with other substances to form lipid domains. The plasma membrane adopts a heterogeneous structure model [72,73][51][52]. You et al. [74][53] reported several new types of lipid–DNA conjugates, termed “DNA zippers”, that can be used to measure the dynamic interactions of cell membranes and the formation of lipid domains in order to study cell membrane lipid domains (Figure 63A).
The lipid raft hypothesis proposes that transient nanodomains with a high concentration of sphingolipids, sterols, and specific proteins exist on the cell membrane [72,75][51][54]. Li et al. [76][55] comprised a DNA nanotweezer composed of a cholesterol-functionalized DNA duplex, which can stabilize short-lived lipid rafts in order to comprehend the potential relationship between lipid rafts and cellular functions. Other spectral tools are useful for further analyzing the components and functions of lipid rafts (Figure 63B). 
Figure 63. (A) Schematic of the DNA zipper system [74][53]. (B) Schematic illustrating the strategy of using DNA nanotweezers to manipulate the cholesterol distribution on a living cell membrane, which stabilizes and dynamically lights up lipid rafts [76][55]. Confocal fluorescence microscopy images of the cells focused on cross and bottom section and schematic illustrating the proposed strategy of using DNA nanotweezers to recruit raft-associated saturated lipids, membrane and possibility endogenous cholesterol. (C) Illustration of the amplified visualization of protein-specific glycosylation via proximity-induced HCR [79][56]. Target proteins are distributed across the cell membrane.

3. Conclusions

Although DNA nanomaterials are widely employed in cell surface fluorescence, the following obstacles must still be addressed. (1) Nowadays, most current imaging strategies involve imaging and analyzing only one or two targets, but using signal amplification techniques, such as HCR and CHA, to achieve the in situ accurate and highly sensitive imaging of multiple targets in the tumor microenvironment remains a challenge. (2) Aptamers must be designed specifically for each receptor. Currently, SELEX technology is used to screen all aptamers, and there are still receptors without aptamers. (3) The majority of DNA nanomaterials are attached to the cell membrane via covalent or noncovalent methods [44,85][57][58] but are susceptible to endocytosis. Even though some scientists have developed polymer molecular skeletons to increase the anchoring time of probes in cell membranes, long-term stability remains a problem. Monitoring intra- and extracellular signaling, cellular morphology, and structural changes requires prolonged in situ imaging, especially for slow-response events such as apoptosis. The creation of probes that can remain attached to the cell membrane for extended durations without being endocytosed remains an area of active research. (4) DNA nanomaterials are used not only for the fluorescence imaging of cell membranes but also for the functional regulation of cell membrane receptors. How to realize the integration of long-term imaging and the functional regulation of cell membranes should also be investigated. (5) FRET is dependent not only on the donor (D)–acceptor (A) separation distance and energetic resonance (i.e., D–A spectral overlap), but also on the orientation of the D emission and A absorption transition dipole moments [86,87][59][60].


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