Chiral Particles to Realize the Promise of Nanomedicine

By Yuwen Wang and Andy Tay, PhD

Chirality refers to the property of an object that cannot be superimposed on its mirror image. Chiral molecules and their mirror images are called enantiomers, which are denoted as “D” (dextrorotatory) and “L” (levorotatory) in Latin nomenclature. The concept of chirality is well established in the fields of organic and stereochemistry, however, its application in biomedicine, particularly nanomedicine, is still in its early stages of development.

In nature, small molecules such as amino acids, carbohydrates, and nucleic acids, which play a crucial role in the origin of life, are chiral. For instance, amino acids are predominantly L, while sugars and the well-known DNA double helix structure are mostly D. This phenomenon is referred to as homochirality and is a defining characteristic of all living things.

Chiral molecules have been widely utilized in drug design, with some molecules designed to interact with the body in an enantiomer-specific manner. For instance, D-Ethambutol is an anti-tuberculosis medication, while L-Ethambutol can induce blindness.¹ The introduction of chirality into nanoparticles (NPs) and nanoassemblies is a promising venue to enhance the translational impact of nanomedicine.

Chiral NPs are synthesized by binding a chiral ligand onto the surface of an NP. In contrast, chiral nanoassemblies denote structures that possess chirality when composed of multiple individual NPs.² The preparation of chiral nanoassemblies can be based on intrinsic chiral interactions, external field induction, or chiral template facilitation, and depending on the driving force leading to the symmetry defect, it can yield a diversity of nanoassembly shapes.³ 

Chiral nanomaterial for immunotherapy

A recent study led by Hua Kuang and Chuanlai Xu from Jiangnan University, and Nicholas Kotov from the University of Michigan, found that NPs with identical chemical structures but different chirality exhibit divergent capacities to stimulate immune cells due to varying atomic spatial arrangements.⁴ The team synthesized monodispersed gold NPs using circularly polarized light and chiral peptides and found that both enantiomers of NPs elicited an immune response, with the L-NP demonstrating a stronger effect than the right-handed enantiomer.

Going further, the team showed that the L-NP was able to enter immune dendritic cells with twice the efficiency than D-NP in vitro and L-NP displayed a 1,258-fold higher efficiency as an adjuvant for the H9N2 influenza virus vaccine compared to the D-NP, offering the potential for the utilization of nanoscale chirality in the field of immunology.

“Chiral nanoparticles and chirality in nanometer scale (not at the angstrom scale typical for optical centers in carbons) is under-explored but critically important area because proteins and other biomacromolecules have it. Thus, we can engineer the NPs to make to interact with the proteins according to the chirality requirements specified by the target protein. Nanoscale chirality enables them to ‘fit’ better. In the case of cancer vaccines, many issues originate from the problem that the good targets on the target proteins (or other macromolecules) exhibit low immune response. This is a reason for many failed cancer vaccines. Chiral NPs can help activate, for example, dendritic cells to ‘learn’ the sequences of target macromolecules to create a more potent vaccine and a more long-lasting curative effect,” says Kotov.

Chiral nanoparticles as cancer treatment and prevention

The utilization of lipid NPs as a drug delivery platform in the context of the COVID-19 pandemic has demonstrated the potential of nanotechnology to revolutionize the field of drug delivery. As various applications of nanotechnology in drug delivery are being explored, lipid NPs have emerged as a promising technology, particularly in the delivery of mRNA vaccines.

Cancer is a significant global health threat and is the second leading cause of death worldwide.⁵ A 2019 study showed that there were 23.6 million new cancer cases and 10 million cancer-related deaths.⁶ While traditional treatments such as surgery, chemotherapy, and radiation therapy are commonly used, these interventions often have severe side effects, largely due to their lack of tumor specificity. To address this issue, researchers are exploring the use of cancer vaccines, which aim to specifically target and eliminate cancer cells through the stimulation of the immune system.

Wang et al., used circularly polarized light to synthesize L-/D-gold NPs capable of performing both therapeutic and preventive functions against tumors in mouse models.⁷ The L-NPs demonstrated stronger interaction with cells, resulting in enhanced activation of NK cells and CD8+ T cells and their infiltration into the tumor tissues.

“Adaptive immunity depends on the recognition of specific antigen. Tumors can escape immune surveillance by cloaking their cell membrane proteins. Thus, there are no desirable target antigens available on the surface of tumor cells. But tumor cells are different from normal cells in some surface protein abundances. We can design chiral nanoparticles targeting tumor cells to release intrinsic antigen, damage associated molecular patterns (DAMPs) and cytokines, and recruit immune cells. The cold immunosuppressive tumor can then be transformed to hot tumor,” says Chuanlai Xu, who led his team to develop chiral nanoparticle for cancer therapy and prevention.

Enantiomer-dependent treatment of Alzheimer’s disease

Alzheimer’s disease is the primary cause of dementia and is a significant health concern in terms of cost, mortality, and burden.⁸ The study of neurodegenerative diseases such as Alzheimer’s disease has recently become a focus for chiral nanotherapeutics. Shi et al., discovered that chiral gold NPs can effectively promote the differentiation of neural stem cells (NSCs) into neurons in mice under near-infrared light irradiation.⁹ NSCs, which possess pluripotency and remarkable regenerative potential, have been proposed as a potential treatment for neurodegenerative diseases, stroke, and spinal cord injury. It was found that the efficiency of cell differentiation increased with the enhancement of chirality, and these chiral NPs also showed significant therapeutic effects in in vivo studies on Alzheimer’s disease mouse models.

In addition to therapy using NSCs, preventing the aggregation of amyloid β (Aβ) peptides is a promising approach for the treatment of AD. The formation of neurofibrillary tangles caused by misfolded aggregates of Aβ peptides is a prominent histopathological feature of AD. A team led by  Zhiyong Tang, a professor from the Center for Nanomaterials in China demonstrated that chiral NPs can effectively inhibit the aggregation of Aβ42 and cross the blood-brain barrier after intravenous administration with minimal toxicity.¹⁰ The L-NPs exhibit a greater binding affinity for Aβ42 and higher brain biodistribution compared to their enantiomeric D-NPs, leading to improved inhibition of Aβ42 fibrillation and more effective rescue of behavioral deficits in AD mouse models.

“The thalidomide tragedy from the last century taught us that different enantiomers of a drug can have vastly different outcomes, with one being effective while the other might be inactive or even harmful. Therefore, determining the chirality of a drug is crucial to ensure its safety and effectiveness. In the field of nanomedicine, chiral nanoparticles have unique characteristics that affect their pharmacokinetics, biodistribution, and efficacy as drug delivery vehicles. Our research has shown that chiral gold nanoparticles exhibit enantioselectivity against amyloid beta aggregation, meaning they preferentially interact with one enantiomer of a drug over the other,” says Tang.  

He adds that most clinical trials using small molecules or antibodies have been unsuccessful against Alzheimer’s disease because the small size of nanoparticles enables them to overcome the body’s barriers and cross the blood-brain barrier, resulting in higher bioavailability and fewer side effects.

“Nevertheless, as with any new therapeutic approach, the safety and toxicity of chiral nanoparticles must be thoroughly evaluated. This includes understanding their potential impact on the immune system, as well as their long-term safety profile. Chiral nanomedicines may also offer noninvasive methods for disease imaging and monitoring, leading to improved patient outcomes and reduced healthcare costs. By minimizing toxicity, chiral nanomedicine has the potential to enhance patients’ quality of life.”  

Challenges and outlook

The use of chiral nanotherapeutics holds significant promise but faces several challenges. For one, the exact mechanism in which cells interact with chiral NPs is not yet fully understood. For instance, a study found that chiral NPs can activate the potassium ion signaling pathway to stimulate immune cells (Xu et al., 2022),⁴ but this is not the typical pathway leading to cytokine release which is typically regulated by calcium channels.¹¹ Hence, it is of great interest to further investigate this phenomenon.

According to Kotov, another challenge is to develop a high-performance toolbox for predicting formations NP-protein complexes with chiral lock-and key fits in which he suggests the need to integrate chirality measures tools and artificial intelligence practices. Additionally, the complexity of synthesizing NPs also makes it challenging to scale up and obtain fast regulatory approval.

All in all, studying the fundamental physicochemical properties of NPs, including size, shape, and surface charge, has become a routine aspect of nanoparticle research.¹² Despite the challenges faced, the potential for chiral nanomaterials to play a role in medicine is significant, and ongoing laboratory studies suggest their viability as a therapeutic tool.

References 

1. Chhabra, N., Aseri, M. L., & Padmanabhan, D. (2013). A review of drug isomerism and its significance. International Journal of Applied and Basic Medical Research, 3(1). https://journals.lww.com/ijab/Fulltext/2013/03010/A_review_of_drug_isomerism_and_its_significance.4.aspx
2. Ma, W., Xu L., de Moura, A. F., Wu, X., Kuang, H., Xu, C. and Kotov, N. A. (2017). Chiral Inorganic Nanostructures. Chemical Reviews, 117, 8041–8093. https://doi.org/10.1021/acs.chemrev.6b00755
3. Lv, J., Gao, X., Han, B., Zhu, Y., Hou, K., & Tang, Z. (2022). Self-assembled inorganic chiral superstructures. Nature Reviews Chemistry, 6(2), Article 2. https://doi.org/10.1038/s41570-021-00350-w
4. Xu, L., Wang, X., Wang, W., Sun, M., Choi, W. J., Kim, J.-Y., Hao, C., Li, S., Qu, A., Lu, M., Wu, X., Colombari, F. M., Gomes, W. R., Blanco, A. L., de Moura, A. F., Guo, X., Kuang, H., Kotov, N. A., & Xu, C. (2022). Enantiomer-dependent immunological response to chiral nanoparticles. Nature, 601(7893), Article 7893. https://doi.org/10.1038/s41586-021-04243-2
5. Vos, T., Lim, S. S., Abbafati, C., Abbas, K. M., Abbasi, M., Abbasifard, M., Abbasi-Kangevari, M., Abbastabar, H., Abd-Allah, F., Abdelalim, A., Abdollahi, M., Abdollahpour, I., Abolhassani, H., Aboyans, V., Abrams, E. M., Abreu, L. G., Abrigo, M. R. M., Abu-Raddad, L. J., Abushouk, A. I., … Murray, C. J. L. (2020). Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. The Lancet, 396(10258), 1204–1222. https://doi.org/10.1016/S0140-6736(20)30925-9
6. Global Burden of Disease 2019 Cancer Collaboration. (2022). Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncology, 8(3), 420–444. https://doi.org/10.1001/jamaoncol.2021.6987
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9. Shi, B., Zhao, J., Xu, Z., Chen, C., Xu, L., Xu, C., Sun, M., & Kuang, H. (2022). Chiral Nanoparticles Force Neural Stem Cell Differentiation to Alleviate Alzheimer’s Disease. Advanced Science, 9(29), 2202475. https://doi.org/10.1002/advs.202202475
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