Chirality in nanoparticles forms the immune response

Molecular shape is of great importance, especially in terms of chirality or chiral homogeneity. A molecule is described as chiral or chiral when there are two forms that are chemically similar but one cannot be applied to the other, and both forms are recognized by their enantiomers and they differ in their interactions with the other molecules. The chirality of molecules has long been used in the design of medicines, and some medicines have even been created to interact with the body in ways that depend specifically on the enantiomers of their molecules. In a paper recently published in the magazine Naturetells researcher Liguang Shu and his research team1 The chiral property can also be used to project nanoparticles with the same chemical composition, although they differ in their ability to activate immune cells, depending on the different arrangement of their atoms.

Nanoparticles show their chiral properties at different levels, both in terms of the interaction of molecules with the cell, and at a much more general level that affects the nature of the molecules themselves. To understand the type of chirality that allows the molecule of interest to interact with the cell requires a special approach during the process of particle synthesis, with the aim of distinguishing the effects of these different forms of chirality. Xu and his research team achieved this goal by using light with a circular polarization of the magnetic field of its waves, that is, in which the magnetic field of the light wave rotates in a plane perpendicular to the direction of its motion. And when we notice the presence of particles or nanoparticles that differ from each other in the way they absorb this kind of light, if its circular polarization is clockwise (left), or counterclockwise (right) , this is an indicator of chirality.these particles. Using this method, the study authors were able to synthesize left and right mirror bonds from gold nanoparticles. This approach also allowed them to vary the degree of asymmetry between these particles by adjusting the parameters of the circular polarized light. This, in turn, enabled researchers to discover the relationship between particle chirality and the strength of the immune response.

The researchers then tested the efficacy of their nanoparticles, experimenting with the immune cells of mice, sometimes in cell cultures and sometimes in live mice. They found that both types of nanoparticle enantiomers were able to stimulate immune responses, but the left enantiomers were stronger than their right-hand counterparts. Different types of measurements proved that the left enantiomer was twice as efficient in entering immune cells as the right one. Further analysis confirmed that this change is due to the chirality phenomenon at the nanoparticle level.

Xu and his research team also examined how gold nanoparticles could affect macrophages and dendritic cells. These two types of immune cells are responsible for the early detection of harmful substances, or fragments of external proteins known as antigens (Fig. 1). Dendritic cells play a critical role in stimulating immune responses that are specific for target antigens. This response, in turn, can lead to the formation of a long-term immune memory, such as what happens after an infection or in response to vaccinations.

Figure 1. Nanoparticles that change in their chiral properties can enhance immune system responsesNanoparticles can activate macrophages and dendritic cells (the two main types of cells within the immune system), to increase the effectiveness of vaccines or immune infections. Xu and his research team explained1, that enantiomers of the left mirror of gold nanoparticles are more efficient in entering immune cells than their right counterparts. Both types of particles interact with receptors known as CD97 and EMR1, which are found on the cell surface, but the isoforms of the left mirror of gold nanoparticles are more efficient at this. The particles are then transported to the cell through a process called intercellular entry. Once inside the cell, these particles send signals to open the ion channels of potassium present in the cell membrane. This, in turn, leads to the activation of NLRP3, a protein-sensing protein complex. Nanoparticles stimulate the cell to produce cytokines (proteins that mediate the growth and activity of immune cells) and increase the rate of co-activating molecules (which activate the immune response of antibodies), two processes needed to activate immune cells known as T cells.

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The researchers also found that the conformations of the left-hand view of gold nanoparticles stimulated the activity of macrophages in vitro, prompting them to produce cytokines, which are proteins that mediate the growth and activation of immune cells. , increases the expression of molecules that stimulate co-activation, in which a signal is generated that activates an immune cellular response when it encounters an antigen-presenting cell. It is known that these two types of responses are required to activate and mobilize immune cells known as T cells. When the researchers injected the living bodies of mice with the isoforms of the left mirror, they obtained results similar to those observed in test tubes.

The researchers then produced nanoparticles, which have different degrees of chirality, depending on a parameter that describes the degree of asymmetry between the degree of absorption clockwise and counterclockwise polarized light. The researchers observed a link between this asymmetry coefficient and the strength of the induced immune response.

The researchers observed that the immune cells absorbed the nanoparticles, through a process called cell insertion, a process that begins by attaching the particles to specific receptors on the cell surface, then they enter a cellular structure known as lysosomes (lysosomes), from which these particles rush into the cell2 The researchers were able to identify two specialized receptors that play a role in this process: CD97 and EMR1. They found that the tendency of the “CD97” receptor to bind to the left nanoparticle conformer was 14 times higher than its tendency to bind to the right conformer, while the tendency of the “EMR1” receptor to bind was connected to the left conformer was 3. times higher than its tendency to connect to the right. This discrepancy explains what the researchers note is that the efficiency of the left modulator to enter the cell is higher than the efficiency of its right counterpart. The researchers also found that the left transgene was more capable of passing through lysosomes.

Xu and his research team were also able to demonstrate that the cellular response to these nanoparticles depends on the inflammatory particle known as “NLRP3”, a complex of proteins that produces inflammatory cytokines in response to signals that detect cell exposure to a form of stress. The researchers found that the NLRP3 particle is activated by opening channels of potassium ions on the cell surface, which leads to the acceleration of potassium ions from the inside to the outside of the cell, a mechanism that has been strongly proven to stimulate the activation process. of inflammatory particles.3 And when scientists suppressed this process, ie the activation of the inflammatory particle, pharmacologically inhibiting “NLRP3”, (ref. No. 44), nanoparticles lost their ability to activate immune cells. In experiments with mice, dendritic cells lacking NLRP3 did not respond to any of the reverse transposons, further evidence of the role of NLRP3 in responding to these nanoparticles.

The response of immune cells to left and right counterparts raises questions about the possibility of using these gold nanoparticles as immunomodulators, i.e. they can be used as ingredients that increase the effectiveness of vaccines, acting as stimulants of the immune system. . Indeed, several tests have been performed to determine the ability of modulators to act as an immune aid other than alum, an alum-containing compound now commonly used as a vaccine booster. The scientists conducted their experiments on a common experimental model of influenza virus infection and found that the left isomer had a stronger effect than its right counterpart, in terms of its ability to stimulate the formation of antibodies against the influenza virus. flu and the efficiency of the left isoform even surpassed that of aluminum.

Although the concept of chirality is often taken into account when designing pharmaceuticals, the study by Xu and his team is the first to show that two chiral nanoparticle enantiomers stimulate two different immune responses. Therefore, nanoparticle chirality can increase the efficiency of current methods in the vaccine production process. The truth is that there are lipid nanoparticles already used in the synthesis of “Covid-19” vaccines, which depend on the RNA sent in their production and it is known that these nanoparticles have an effect that enhances the immune response.5 But its most prominent role6In this context, it must act as a protective point, preventing the sent RNA from breaking down.

Nanoparticles can offer us a dual benefit, as they improve the absorption of vaccines in the body and increase their efficiency and effectiveness. Furthermore, the role that nanoparticles play as mediators in NLRP3 activation may strengthen the arguments for the use of nanoparticles as immunostimulants.7 However, activation of NLRP3 can simultaneously lead to detrimental inflammatory responses, so the role the authors have discovered may benefit from studies investigating potential nanoparticle toxicity.

With the increasing use of nanoparticles in different contexts, such as cosmetics manufacturing, the textile and electronics industry, for example, the rate at which we are exposed to nanoparticles every day is increasing at the same time. Although some nanoparticles can distort the proper function of immune cells, or suppress immunity8Others can stimulate the immune system9, such as those covered in the study by Shaw and his research team. Such nanoparticles can be useful in maximizing the area of ​​influence of immune responses, and then we can utilize them to improve the effectiveness of vaccines, or even to improve cancer immunotherapy. As Shaw and his team point out, chirality is a key property of nanoparticles used to activate immune cells, a discovery that will undoubtedly guide efforts to design versatile nanoparticles.

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