Potential immuno-nanomedicine strategies to fight COVID-19 like pulmonary infections

Abstract

COVID-19, coronavirus disease 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a pandemic. At the time of writing this (October 14, 2020), more than 38.4 million people have become affected, and 1.0 million people have died across the world. The death rate is undoubtedly correlated with the cytokine storm and other pathological pulmonary characteristics, as a result of which the lungs cannot provide sufficient oxygen to the body's vital organs. While diversified drugs have been tested as a first line therapy, the complexity of fatal cases has not been reduced so far, and the world is looking for a treatment to combat the virus. However, to date, and despite such promise, we have received very limited information about the potential of nanomedicine to fight against COVID-19 or as an adjunct therapy in the treatment regimen. Over the past two decades, various therapeutic strategies, including direct-acting antiviral drugs, immunomodulators, a few non-specific drugs (simple to complex), have been explored to treat Acute Respiratory Distress Syndrome (ARDS), Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), influenza, and sometimes the common flu, thus, correlating and developing specific drugs centric to COVID-19 is possible. This review article focuses on the pulmonary pathology caused by SARS-CoV-2 and other viral pathogens, highlighting possible nanomedicine therapeutic strategies that should be further tested immediately.

Keywords: COVID-19; Coronavirus; Influenza, Pulmonary drug delivery; MERS, Nanomedicine; Nanotechnology; Nanotherapeutics; Pathophysiology; SARS, SARS-CoV-2.

Graphical abstract

Fig. 1

Lung pathology in COVID-19. The lungs of severely ill COVID-19 patients appear to be opaque in the CT scan. SARS-CoV-2 enters via the nose, mouth, or eyes and reaches the alveoli, where a high expression of ACE2 receptors are present. Alveoli exist in the form of balloon-shaped structures. In any lung infection, different cells and substances are involved in protective immunity as well as inflammation. Invading SARS-CoV-2 interacts with, especially, tracheobronchial and alveolar epithelium and subsequently induces damage (apoptosis/necrosis) to the cells. The damage affects the tight barrier integrity of both the endothelium and epithelium layers. The epithelium is composed of a monolayer of alveolar type I and alveolar type II cells, which perform gas exchange and the production of surfactant functions, respectively. These functions keep the air space dry in the lungs. The damaged cells produce danger signals, such as reactive oxygen/nitrogen species, which recruit the innate immune cells, such as monocytes, immature macrophages, neutrophils, and dendritic cells. Upon uncontrolled activation, immune cells, epithelial cells, and fibroblast cells secrete copious amounts of pro-inflammatory cytokines and chemokines, which in turn act as a causative factor for epithelial cell death. In addition, they block the functional Na⁺/K⁺-ATPase pump, which keeps the osmotic equilibrium in the alveolus. The impaired tight junctions lose their fluid resistance nature and allow the fluids into the alveolus leading to edematous inflammation, which obstructs the vital gas exchanges process. Note: This hypothetical figure illustration is based on the output obtained from different non-peer reviewed publications and in comparison of other lung diseases, such as ARDS, SARS, MERS, influenza. Abbreviations: ATI, alveolar type I cell; ATII, alveolar type II cell; BASC, bronchioalveolar stem cell; BM, basement membrane; EBM, endothelial basement membrane; ECM, extracellular matrix, NETs, neutrophil extracellular traps; RBC, red blood cell; ROS, reactive oxygen species.

Fig. 2

Therapeutic strategies for COVID-19. SARS-CoV-2 uses epithelial cells, particularly lung epithelial cells, for their propagation. During the replication process, virus particles induce cell death signals to release pro-inflammatory cytokines and DAMPs, which in turn are sensed by the macrophages, monocytes, and neutrophils followed by the activation of other bystander cells and the development of the systemic cytokine storm. Based on the life-cycle of SARS-CoVs, the above-proposed drugs have been used in clinical trials. Note: As detailed, the immunological responses of SARS-CoV-2 have not been established yet; thus, studies illustrated are in comparison with SARS and MERS. More details can be found in the text and Table 1. Abbreviations: ACE2, angiotensin 1-converting enzyme 2; CTL, cytotoxic T lymphocytes; DAMPs, danger-associated molecular patterns; ER, endoplasmic reticulum; NETs, neutrophil extracellular traps; RNA, ribonucleic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Fig. 3

Nanomedicine based strategies to prevent the pathologies associated with respiratory infections. A variety of viruses from different sources are responsible for respiratory infections. A few viruses, such as rhinovirus, parainfluenza virus, coronaviruses, adenoviruses, coxsackievirus, respiratory syncytial virus, herpesvirus, bocavirus, and others, particularly infect the upper respiratory tract. On the other hand, avian influenza virus, parainfluenza virus, respiratory syncytial virus, bocavirus, adenoviruses, metapneumovirus, and others infect the lower respiratory tract. In both the cases, they cause the common cold, bronchitis, bronchiolitis, and sometimes-severe pneumonia. Furthermore, the infection results in the dysfunction and damage to the other vital organs. Nanomedicine-based strategies that are explained above target the pathologies and reduce the severity of the disease. Abbreviations: NP, nanoparticle.

Fig. 4

Diversified application of nanomedicine in combating respiratory infections. a) Schematic diagram of the inhibition of MERS-CoV S2 subunit-mediated membrane fusion with HR1 inhibitors. HR1 inhibitors can inhibit HR1/HR2 complex (6-HB)-mediated membrane fusion and prevent MERS-CoV infections. b) Strategy to detect the corona infection by colorimetric detection of double stranded DNA based on disulfide-induced self-assembly and shielding of AuNPs from salt-induced aggregation. In the absence of targets (virus), salt induces aggregation of AuNPs. c) Mechanisms of action of different nanoparticles. The design and use of nanomedicine approaches help in enhancing the delivery system targetability and therapeutic efficacy in lung-associated infections. The drug loaded nano vehicles can be passively or actively targeted to the pulmonary epithelium to enhance the permeation and localized drug release thereby reducing associated side effects. Inorganic nano-systems are useful in the diagnosis of virus infections and also have inhibitory effects on the virus. The virus like particle systems (VLPs) enhance the immune response to combat lung-associated infections. d) Strategies to combat the COVID-19-like respiratory infectious diseases. Nanomedicine can play a potential role in the diagnostic and therapeutic of COVID-19 like diseases. NPs are useful for the development of different sensors to detect SARS-CoV-2-like infections and, thus, can be used for an early real-time detection of a virus with precession. A therapeutics approach at the moment is based upon post functionalization strategies by using different biomolecules and small molecule inhibitors to prevent the entry of the viruses inside the host cells and to block viral replication. Abbreviations: AuNPs, gold nanoparticles; COVID-19, coronavirus disease 2019; DDP4, dipeptidyl peptidase four receptors; 6-HB, 6-helix bundle; HR, heptad repeat; QDs, quantum dots; MERS-CoV, Middle East respiratory syndrome-related coronavirus; NPs, nanoparticles; VLPs, virus-like particles.

Fig. 5

The effect of EDA-CDs on PEDV. (a) The effect of different concentrations of EDA-CDs on PEDV-infected Vero cells by indirect immunofluorescence assay. Scale bar: 100 µm. (b) The titers of PEDV when exposed or unexposed to 125 µg/mL EDA-CDs or CCM-CDs. All error bars were determined according to the three replicate experiments. ** p < 0.01 and indicates superior antiviral activity of CCM-CDs to EDA-CDs treated and untreated, against PEDV. (c) Virus titers were calculated in the presence and absence of EDA-CDs or CCM-CDs. Pictures were taken at 12 hpi. Abbreviations: CCM-CDs, curcumin carbon dots; EDA-CDs, ethylenediamine carbon dots; PEDV, porcine epidemic diarrhoea virus.