Immunoregulatory nanomedicines for the prevention and treatment of respiratory diseases

By Dr. Priyom Bose, Ph.D.Dec 7 2023Reviewed by Benedette Cuffari, M.Sc.

In a recent study published in the journal Nature Reviews Bioengineering, researchers explore various aspects of immunoregulatory nanomedicines against respiratory illness.

Study: Immunoregulatory nanomedicine for respiratory infections. Image Credit: mi_viri / Shutterstock.com

Respiratory diseases and immunotherapeutics

Respiratory infections are one of the leading causes of global mortality and morbidity. Moreover, these illnesses significantly affect the global economy, social development, and healthcare systems.

Respiratory diseases are caused by various pathogenic viruses, bacteria, and fungi, the most notable of which include Middle East respiratory syndrome (MERS) coronavirus, H1N1 influenza, severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, pulmonary aspergillosis, tuberculosis, and bacterial pneumonia.

Vaccination and immunotherapy are effective immune-based strategies to prevent and treat infectious respiratory diseases. These immunoregulatory treatments manipulate the therapeutic functions of the immune system, as vaccination stimulates adaptive immunity to protect against pathogenic infestation.

There are different types of vaccines based on differential developing strategies, such as whole-inactivated pathogens, live attenuated pathogens, recombinant bacterial vectors, recombinant viral vectors, synthetic peptides, DNA, and messenger ribonucleic acid (mRNA).

Typically, subunit vaccines have limited immunogenicity, as they contain fewer antigens, thereby preventing them from producing significant immune protection against the pathogen. Recently, SPIKEVAX and COMIRNATY, both of which are two nanovaccines, received approval from the United States Food and Drug Administration (FDA) for the prevention of the coronavirus disease 2019 (COVID-19).

Antibody treatments are effective in treating early-stage viral infections. In addition, immune potentiator molecules, such as Toll-like receptors and inflammation modulator molecules, including interleukin-1 (IL-1) or IL-6 receptor antagonists, are used to treat respiratory illness. These strategies are associated with translational challenges that lead to reduced antibody titers in plasma over time and insignificant therapeutic efficacy due to viral mutations.

Nanomedicines based on different nanocarriers

Nanomedicines are designed to enhance the therapeutic outcomes of drugs, primarily by improving drug loading capacity and release, which enhances their pharmacokinetic properties. Peptides, micelles, cell membranes, extracellular vesicles, liposomes, and polymers can be designed as nanocarriers. A nanocarrier can regulate the immunological environment for effective respiratory disease treatment.

Ionizable nanoparticles (iLNPs) are commonly used to deliver mRNA, as they protect this genetic material against non-specific protein binding. This nanocarrier is electrically almost neutral, and negatively charged mRNA is loaded under acidic pH conditions. The nebulization technique is used to efficiently deliver mRNAs from iLNP to the lungs.

Cationic polymers are used to deliver nucleic acid for therapeutic purposes; however, this technique is rarely used in clinical settings due to the risk of toxicity observed in vivo. A recent study revealed that a nanocarrier containing polyethyleneimine (PEI) was used to deliver a plasmid DNA vaccine through the intranasal route for COVID-19 prevention and treatment.

Protamine is a positively charged small protein that is rich in arginine. This protein is used to deliver mRNA for the prophylactic vaccination against respiratory illness caused by influenza A H1N1, H3N2, and H5N1 viruses. Polycation-functionalized zirconium (Zr)-based metal-organic frameworks and DNA-decorated gold nanoparticles have also been explored for mRNA delivery.

Nanomedicines-regulated immune system

A local inflammatory response arises during lung infection if alveolar macrophages fail to control pathogenic growth. Initially, alveolar epithelial cells are activated by recognizing pathogen-associated molecular patterns (PAMPs).

Macrophages, activated alveolar epithelial cells, and other immune cells secrete pro-inflammatory cytokines to bring more immune cells to the infected lung tissues. In some cases, massive production of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) cause aggressive inflammatory response syndrome, which can lead to severe respiratory infections and even death.

Immune-regulating nanomedicines can improve therapeutic efficiency by blocking pro-inflammatory signaling pathways and inhibiting the entry of viruses. Nanomedicines can modulate hyperactivated immune cells and scavenge unsolicited immune molecules. Nanotherapeutics can also inhibit neutrophil function by downregulating superoxide anions, thereby suppressing neutrophil elastase and blocking β2 integrin signaling, which helps reduce persistent lung inflammation.

The size of nanoparticles affects neutrophil deactivation. For example, small nanoparticles loaded with oleic acid exhibited greater neutrophil deactivation by suppressing the production of superoxide anions and neutrophil elastase. Comparatively, larger nanoparticles accumulate in the lung tissues without alleviating lung infection.

Conclusions

Several studies have shown that the application of immune-regulation strategies could significantly improve the prevention and treatment of infectious respiratory diseases. An effective application of nanoparticles, particularly for drug delivery, can dramatically improve disease outcomes. 

Nanovaccines can activate both B-cell and T-cell responses and can be easily modified in accordance with new viral mutations. Inhalable nanovaccines can also be developed to deliver antigens directly into the lungs; however, these vaccines must be equipped to overcome the barriers of the mucosal system. 

More research is needed to determine the safety profile of these vaccines and their possible distribution to the central nervous system. In the future, artificial intelligence can be used to select and design antigen molecules for the development of effective nanovaccines.