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Can we develop a cellular nano-sensing mechanism to specifically detect and target viral markers (NA and proteins) to fight viral infections in vivo?

Image credit: https://www.dovepress.com/cr_data/article_fulltext/s56000/56771/img/fig3.jpg

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Subash Chapagain
Subash Chapagain Nov 04, 2020
Can we plug nanosensors in the tissue/cells in the host body to automatically detect and fight viral infections?

Nanotechnology, by definition, is the field of study that deals with the manipulation of matter at the molecular and atomic levels. In the last two decades, the scope of nanotechnology has escalated, involving the production and application of the physical, chemical, and biological systems at a 1-100 nanometer scale. The ultra-small materials, usually called nanoparticles or nanomaterials, offer researchers and scientists exceptional physical, chemical, and biological properties vis a vis their bulk counterparts . Nanomaterials have lately found a wide range of potential applications in biomedicine, optical and medical imaging, catalysis, and electronics. Their small size enhances the performance of other electrochemical and enzymatic processes by increasing electron transfer rates and also by shortening enzyme-to-electrode distances .

By the virtue of their improved catalytic properties, robust electron transfer and their capability to be used in biomolecule labeling and adsorption, nanoparticles are well suited to be used for biosensing purposes. Initiated with the introduction of glucose oxidase biosensor in the 1960s, the research journey of biosensors has till now been an intriguing journey with many interesting biological sensors being invented and commercialized. The biosensor can be aptly defined as “an analytical device (or a system) that includes a biologically active component in close contact with an appropriate physicochemical transducer to generate a measurable signal that is proportional to the concentration of the target substance in the environment .”

Typically, a biosensor consists of three components: a biological recognition component (usually an enzyme, antibody, or Nucleic Acid), a sensor element for signal acquisition (electrical/optical/thermal), and an element for signal amplification/manifestation. Several biosensors have already been commercialized for in vivo applications, mainly for usage in real-time glucose level monitoring .

Using nanotechnology and biosensor technology simultaneously, could we similarly engineer a target group of cells/tissues in vivo to house a biosensor that can detect the presence of viral nucleic acid (or any other viral component)?

So, the scope (and intent) of this session is to try and accumulate overarching principles and methods that can be used to create an in vivo system for a nano-sensing mechanism that can detect and potentially ward off the infection by targeting the viral Nucleic Acids. To start with, I propose one idea: we can use exosomal (vesicles) engineering to create vesicles that contain these nano biosensors that detect and eventually silence/destroy the viral nucleic acids. The detection target would be any marker component in the viral genome. After the detection, we can further couple it to incite a specific set of immune system components to target and destroy the viral nucleic acid. If designed aptly, this kind of system could come in handy to cure persistent and latent viral infections. In the case of persistent viral infections, the viral genome often gets silently integrated within the host genome and is expressed under any suitable conditions. The expression is controlled by the promoter region of the viral genome. Take for example the case of latent HIV infection where the HIV is silently integrated into the host cell as a proviral DNA that may not immediately express and transcribe, but can cause recurring infections in the later stage of the host’s life. The HIV genome contains the HIV LTR with upstream DNA regulatory elements that serve as binding sites for cellular transcription factors. The core promoter consists of SP1 binding sites, an efficient TATA element, and a highly active initiator sequence. Hence, these specific elements can be targeted by the nano biosensor in vivo, potentially cleansing the cells that harbor these proviral DNA. However, before such a potential nano biosensing mechanism is fully realized, we might have to address several design questions:
  • how do we make such a biosensor self-contained?
  • how do we guarantee zero degrees of hyperimmune activation?
  • how do we ensure biocompatibility?
What other research questions can we ask to reach the goal of such a nano-inspired biosensing mechanism in vivo? How can we make it possible?

[1]A. I. Usman, A. A. Aziz, and O. A. Noqta, “Application of green synthesis of gold nanopartciels: a review,” Jurnal Teknologi (Sciences & Engineering), vol. 8, no. 1, pp. 171–182, 2019.

[2]L. Murphy, “Biosensors and bioelectrochemistry,” Current Opinion in Chemical Biology, vol. 10, no. 2, pp. 177–184, 2006.

[3]Wilson GS, Gifford R. Biosensors for real-time in vivo measurements. Biosens Bioelectron. 2005;20(12):2388–2403.

[4]Mastrototaro, J.J., 2000. The MiniMed continuous glucose monitoring system. Diabetes Technol. Ther. 2, S13–S18.

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Creative contributions

A stent-based detector of viruses using Luminescent quantum dots (Qdots)

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J
J. Feb 17, 2021

Introduction

AIDS is, unfortunately, one of the most popular uncurable diseases nowadays. It's caused by Human Immunodeficiency Virus (HIV) that, along with many other actions, damages CD4+T lymphocytes, whose number can give doctors valuable information on the disease progression. Because many factors can influence CD4+T lymphocyte count, doctors use additional "number of HIV per unit of volume" to more precisely determine the stage of the disease and the best therapy .

Until now, antibodies targeting specific gp120 glycoproteins (one of the two most known proteins found on HIV lipid membrane envelop) that directly mediate recognition of CD4 receptors on target cells, have been used to visualize and target HIV. The gp120 protein is glycosylated by high-mannose oligosaccharides and they can also help in specifically detecting HIV, but all the available dyes and fluorescent proteins are not suited for long term imaging .

To overcome this problem, researchers developed Luminescent quantum dots (Qdots). They are CdSe ZnS-coated semiconductor nanocrystals that are characterized by photostability and narrow multicolor emission spectra. Although they are extensively used in immunolabelling, in vitro and in vivo studies , few studies used Qdots for real-time virus detection in microfluidic devices .

Clue no. 1
But, paper from 2010 described exactly that - an integrated microfluidic device that can visualize HIV from the HIV-infected patient whole blood within 10 minutes . They demonstrated real-time capture of the HIV in so-called "immunosandwich" made of anti-gp120 bound to the surface of the microfluidic device and Qdot-conjugated anti-gp120 (Figure 1).

Figure 1. The "immunosandwich" that captures HIV. Taken from .

Clue no. 2
One of the most implantable things generally, but especially to battle coronary diseases, is a stent. Except for various materials that would stop late stent thrombosis , papers tried to add various add-on features to a stent. Interestingly, a paper from 2016 suggested an in-vivo monitoring system for blood glucose levels by using a wirelessly-powered stent (Figure 2).
Figure 2. Wirelessly-powered real-time glucose monitoring stent. Taken from .


The proposed concept

The idea is to make "immunosandwich" real-time detection of HIV directly in blood vessels.

The moving part
Antibody-conjugated Qdots with high sensitivity and long-lasting signal which circulate in the bloodstream and bind to the target viral proteins.

The stationary part
Wirelessly-powered stents with multiple separate channels coated with different antibodies against known viruses. Blood would enter and exit the microchannel without big blood-flow disruption, while detected viruses would accumulate in the channel.

Pluses

High sensitivity and long-lasting signal - accumulative real time detection

Minuses

Antibody-conjugated Qdots bind to the proteins irreversibly - one-time detection
Antibody-conjugated Qdots could accumulate in the organism - they should be soluble in water
Antibody-conjugated Qdots concentration will be reduced by time - repeated intake
Stents could cause late stent thrombosis - necessary to develop more suitable materials
_________________
What do you think?

[1]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746625/

[2]https://pubs.acs.org/doi/full/10.1021/nl034987p

[3]https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(12)00075-3

[4]https://www.semanticscholar.org/paper/A-stent-based-in-vivo-bio-sensing-system-for-Jang-Na/4f6980cc2c629629b7df11b6d8b6bb8afd18b793

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JA
Jon Ashley2 months ago
Qdots have one major drawback at the moment which limits their in vivo use. They are quite toxic to the body. Especially the Cd containing Qdots.
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J
J.2 months ago
Jon Ashley well, that could be a major problem, I agree. Do you have anything on your mind on how to solve it, or a paper that could help?
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Subash Chapagain
Subash Chapagain3 months ago
Thanks for this input, Juran.

This looks like one viable option. Stents could work like you said if we could develop from the already existing ones to conjugate detection systems (primarily antibody-antigen kind of interactions). The immunosandwich is one technique that I have routinely used in lab experiments, and if we could modify the same technique to use in vivo for real-time monitoring, that would be great. However, these detection systems (at least in the lab) need secondary reagents/washes/buffers and dyes for detection by the detector system (note that usually, it is the spectroscopic features of the sample being analyzed); as well as most of this systems are exhaustive. Hence, while using stents as the platforms for such detection in vivo, I think first we need to figure out ways to do so without any toxic dyes (or develop dyes/buffers/reagents that are absolutely biocompatible).

From your proposed concept, the future direction for this approach would be to investigate if there are any existing mechanisms to make these Qdots durable and consistent over a larger time frame. Also, the signal decay ( given that most of the detection is an electrochemical one, which dissipates with time) poses another difficulty in monitoring- meaning that the system must have an instantaneously transmissible output system that can be monitored in real-time. This is particularly where the idea of prosthetic nanodevices as you mentioned in your session could come in handy.



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