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The potential role of nanomedicine on
COVID-19 therapeutics
Rubiana Mara Mainardes*,1 & Camila Diedrich1
1Pharmaceutical Nanotechnology Laboratory, Universidade Estadual do Centro-Oeste, Alameda ´
Elio Antonio Dalla Vecchia,
838 - CEP, Guarapuava PR 85040-167, Brazil
*Author for correspondence: mainardes@unicentro.br
“Although it is well-established that nanotech-based drug-delivery systems improve existing
therapeutics in medicine, its application in viral diseases is underexplored and underused”
First draft submitted: 3 June 2020; Accepted for publication: 15 June 2020; Published online:
29 June 2020
Keywords: COVID-19 •drug delivery •nanoparticles
Since December 2019, several cases of a different type of pneumonia were reported in Wuhan, Central China [1].
Patients symptoms included fever, dry cough, dyspnoea and gastrointestinal issues [2]. Within days, the authorities
confirmed that a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV-2) caused the
outbreak [1]. SARS-CoV-2 virus is the agent responsible for the coronavirus disease termed COVID-19 [2].
Main features of COVID-19
SARS-CoV-2 belongs to Coronaviruses (CoV), a ssRNA family of viruses that infect animals and humans [3].The
CoV family is organized into four genera: alpha-coronavirus , beta-coronavirus (β-CoV), gamma-coronavirus and
delta-coronavirus (δ-CoV). Alpha-coronavirus and β-CoV genera are responsible for infections in mammals [4].
SARS-CoV-2 is classified as β-CoV, the same genera as SARS-CoV and middle east respiratory syndrome (MERS-
CoV), the respiratory syndromes that caused outbreaks in 2002 in China and 2012 in Saudi Arabia, respectively [5].
SARS-CoV was first identified in Guangdong, China, in 2002 and infected 8098 individuals in 26 countries
worldwide, leading to a mortality rate of 9.0% [2]. MERS-CoV first appeared in Saudi Arabia in 2012 and
circulated along the Arabian Peninsula, resulting in 2494 cases, of which 858 were fatal, reaching a mortality
rate higher than 35.0% [1]. Although SARS-CoV-2 has been reported to have over 80.0% similarity with the
genome of SARS and 50.0% similarity with MERS [6], it presents higher transmission and infection rates, but a
low fatality percentage, according to published reports [7]. On the other hand, the reproductive number (R0)of
SARS-CoV-2 is estimated to be 2.2, while SARS-CoV and MERS-CoV have an R0of 1.8 and <1, respectively [8].
In addition, SARS-CoV and MERS-CoV spread in hospital environment, whereas SARS-CoV-2 is transmitted in
the community, due to the less severe symptoms [8]. The high R0added to the large number of asymptomatic and
subclinical cases, as well as lead to the great pandemic potential of COVID-19.
To infect a system, a virus binds to a receptor in a host cell, merging with the cell membrane [5].SARS-CoV-2
and SARS-CoV have the same human cell receptor, the angiotensin-converting enzyme 2, known as ACE2, while
MERS-CoV enters into the cell through the dipeptidyl peptidase 4 (DPP4) receptor [2,8]. The main difference
between MERS-CoV and SARS-CoVs receptors is that the DPP4 receptor for MERS-CoV is highly expressed in the
kidney, resulting in severe kidney injury [8]. The ACE2 receptor is used for SARS-CoV and SARS-CoV-2 to access
the lung epithelial cell, where the virus replicates rapidly, leading to tissue injury [4]. Recent findings indicate that
SARS-CoV-2 binds to ACE2 at a rate tenfold higher than SARS-CoV [7], which explains its faster human-to-human
spreading [1,4]. Once the lung epithelium is damaged, the immune response soon brings about pro-inflammatory
cytokines, causing acute respiratory distress syndrome and multiple organ failure [4,8]. This immune response
to SASR-CoV-2 is announced by laboratory indicators, such as lymphopenia in 81.0% of patients, followed
by a decrease in platelet count and albumin levels, as well as increased aminotransferases, lactic dehydrogenase,
creatine kinase and C-reactive protein levels [5,7–9]. Regarding radiological characteristics, COVID-19 indicators
Ther. Deliv. (Epub ahead of print) ISSN 2041-599010.4155/tde-2020-0069 C
2020 Newlands Press
Commentary Mainardes & Diedrich
are pulmonary lesions including bilateral ground-glass opacity in 68.5% of the cases, followed by consolidations,
smooth or irregular interlobular septal and adjacent pleura thickening [7,8]. Additionally, 32.8% of patients present
acute respiratory distress syndrome and 13.0% show acute cardiac injury [9].
Due to its fast spreading, the early identification of SARS-CoV-2 cases is currently the best way to prevent
COVID-19 from advancing. Under this urgent circumstance, many detection methods have been developed to
control the SARS-CoV-2 outbreak [10]. COVID-19 virus detection is performed using samples such as swabs, nasal
swabs, nasopharynx or trachea extracts, sputum or lung tissue, blood and feces from suspected patients [3].The
most applied method of laboratory diagnosis is the nucleic acid detection through reverse transcription-quantitative
polymerase chain reaction [4]. Meanwhile, the specific high sensitivity enzymatic reporter unlocking technology,
developed by Massachusetts Institute of Technology, MA, USA experts, offers rapid investigation of the virus using
synthetic SARS-CoV-2 RNA fragments, reducing the diagnosis time [7]. Through SARS-CoV-2 identification, the
virus is differentiated from other diseases, for instance, influenza, bacterial pneumonia, adenovirus, rhinovirus and
other noninfectious illness [3]. Importantly, the reduction of recognition time seems to be essential, since the rapid
spread of COVID-19 [11].
Therapeutics of COVID-19
Although all populations are susceptible to COVID-19, studies point to its prevalence in patients with comorbidities
such as hypertension, diabetes, respiratory system disorders and heart illness [10]. The median age reported for
COVID-19 patients is around 51.2-year old, being male in 55.9% of cases [7,9]. Studies also indicate that the
disease incubation period is around 3.0–7.0 days, taking 14.0–20.0 days from first symptoms to death in fatal
cases [4]. However, in people over 70-year old, this time decreases to 11.5 days [7].
So far, no treatment for COVID-19 has been considered effective and several strategies are being tested [11].In
the beginning of the global outbreak, the WHO announced that a vaccine for SARS-CoV-2 might be at hand in
18 months, however as the structure of virus has been revealed, rapid strategies targeting the spike glycoprotein
have been optimized [1] and many are under clinical trials. To date, the adopted treatment is the application of
broad-spectrum antiviral drugs. Among the tested antiviral drugs used is interferon, which has shown to be effective
against CoVs [10,11] and has been recommended by The National Health Commission of the People’s Republic of
China in addition to lopinavir and ritonavir protease inhibitors [12]. Ribavirin, a nucleoside analogue, was used
to treat SARS-CoV in Hong Kong, representing another option [4] combined with protease inhibitors [12].The
National Medical Products Administration of China approved favilavir for marketing at the beginning of the
COVID-19 outbreak [10]. Another drug under test is Arbidol, which reduces the reproduction of SARS in vitro [7].
Remdesivir, a nucleotide analogue developed for Ebola virus, was reported as a potential treatment for COVID-19,
since it demonstrated the blocking of SARS-CoV-2 replication when combined with interferon or chloroquine,
as well as alone [2]. Other antiviral drugs under test are nafamostat, nitazoxanide, penciclovir, oseltamivir and
baricitinib [2,12]. The number of registered clinical trials using antiviral drugs for the treatment of patients with
COVID-19 is 195, up to 3 June 2020.
The antimalarial drugs chloroquine and hydroxychloroquine were considered by recent publications world-
wide [13] and are included in the recommendations for the prevention and treatment of COVID-19 pneumonia
in several countries. These drugs alter the endosomal and lysosomal pH, preventing viral fusion and inhibit the
endocytosis mediated cell uptake of SARS-CoV-2 [14]. However, the lack of results from well-performed randomized
trials make it difficult to support the use of these drugs, especially considering their well-known cardiac toxicity.
Besides antiviral drugs, other approaches have been investigated to treat COVID-19. Antiviral antibodies
produced in recovered patients, for example, were isolated from their blood plasma, exhibiting positive results [2].In
addition, umbilical cord blood, rich in natural killer cells and mesenchymal stem cells, represent the body’s defense
activity against SARS [4]. Regarding antibiotic therapy, a broad spectrum of antibiotics are indicated, only in case
the patients develop bacterial or fungal infections during advanced stages of COVID-19 [12]. In the same way, the
administration of corticosteroids must be avoided, except in cases of urgency due to adverse effects [10].Hence,a
review study revealed that more than 85.5% of patients were treated with antiviral agents, while empirical antibiotics
were prescribed in 90.0% of cases [6]. With the aim of testing different mechanisms to combat SARS-CoV-2, the
WHO has announced a clinical trial design to be joined by doctors from around the world [13].
10.4155/tde-2020-0069 Ther. Deliv. (Epub ahead of print) future science group
The potential role of nanomedicine on COVID-19 therapeutics Commentary
The role of nanomedicine in COVID-19
Nanomedicine impacts all fields of medicine, and has been considered an important instrument for novel diag-
nostics, medical imaging, nanotherapeutics, vaccines and to develop biomaterials for regenerative medicine [15].
Soft nanomaterials obtained from polymers (polymeric nanoparticles), lipids (lipid-solid nanoparticles, nanostruc-
tured lipid carriers, liposomes), surfactants (microemulsion, nanoemulsions, liquid crystals) and proteins (protein
nanoparticles) have been applied in nanomedicine, especially for drug delivery. The magnitude of interactions be-
tween nanomaterials and tissues/biological molecules is the base for their use for various medical applications [16].
Drug-based nanoparticles have been developed for decades, and several are under clinical trials for cancer, neurode-
generative, inflammatory, cardiovascular and infectious diseases, although only few of them are approved for human
use [13]. The improvement of biopharmaceutical, pharmacokinetic and pharmacodynamic aspects of drug loading
is the main tool of soft nanomaterials. Also, nanoparticles can promote specific drug targeting (passive or active
targeting) and controlled drug-release rate, thereby, affecting the efficacy and safety of the treatment. Besides soft
and metal nanoparticles have been applied in nanomedicine, mainly due to their various antimicrobial activities
(antibacterial, antifungal, antiparasitic and antiviral) [13].
Due to the emergence of pathogenic bacteria resistant to antimicrobials, several studies have reported the
efficacy of the nanotechnology-based antimicrobial therapy. Similarly, the occurrence of new viruses and their
heterogeneity has also demanded innovative therapies. This way, considering specific targeting, nanotechnology
opens a new avenue for antiviral therapy. The strategy of using nanoparticles to combat SARS-CoV-2 could involve
mechanisms that effect the entry of the virus into the host cell until their inactivation. The blockage of the viral
surface proteins may lead to virus inactivation, so targeted nanoparticles, specific to virus expressed proteins could
reduce the viral internalization [17]. Metal nanoparticles have shown the ability to block viral attachment to the cell
surface, leading to the inhibition of viral internalization and thereby impairing the viral replication during viral
entry. Nanoparticles composed of titanium (Ti), silver (Ag), gold (Au) and zinc (Zn) have already shown results
against the HIV, influenza virus, herpes simplex virus, respiratory syncytial virus, transmissible gastroenteritis virus,
monkey pox virus and zika virus [13]. The mechanism of action is based on the nanoparticles binding onto the
viral envelope or its protein, impairing the interaction with the host cell. The efficacy of the treatment is related
to the size, shape and the surface charge of the nanoparticles, however, safety measures must be taken regarding
the concentration to avoid cytotoxicity of host cells [18]. Organic nanoparticles have been used for delivering
antivirals such as zidovudine, acyclovir, dapivirine and efavirenz, with the aim to improve drug bioavailability and
promote efficient drug delivery and targeted antiviral activity [19]. The main limitations of antivirals are the lack of
specific targeting, resulting in cytotoxicity of the host cell, which can be addressed by organic nanoparticles. The
versatility of nanoparticles makes them tunable vectors for virus targeting and specific drug delivery. Antimicrobial
drugs have been tested in clinical trials for COVID-19, such as chloroquine, lopinavir, ritonavir, ribavirim and
remdesivir, and have demonstrated promising results against SARS-CoV-2 [4]. Nanoencapsulation of antimicrobial
drugs may contribute to the development of safer treatments for COVID-19 and other viral diseases.
Although it is well-established that nanotech-based drug-delivery systems improve existing therapeutics in
medicine, its application in viral diseases is underexplored and underused, as observed in the SARS-CoV-2 pandemic.
Nanostructured systems can impact diagnosis, since they can improve the detection, sensitivity and increase the
signal amplification specificity in polymerase chain reaction analysis; and prophylaxis as adjuvants for vaccines, as
well as therapeutics for COVID-19 through the targeting of antiviral drugs [20].
In summary, nanoparticles may play an important role at different stages of COVID-19 pathogenesis, considering
their inhibition potential in the initial attachment and membrane fusion during viral entry and infected cell protein
fusion. Furthermore, nanoencapsulated drugs may be more efficient in activating intracellular mechanisms to cause
irreversible damage to viruses and inhibition of viral transcription, translation and replication.
Conclusion
To date, there are no specific approved drugs for treating SARS-CoV-2, and vaccines are under clinical trials.
All efforts are welcome to combat the virus, and nanotech-based approaches would bring a new perspective
to conventional medicine for the inhibition of virus internalization or treatment. More studies are required to
understand the interface between nanoparticles and CoV, to trace a rational design of targeted therapeutics.
Certainly, a pandemic involves whole health organizations and as the pathogenesis of SARS-CoV-2 is not well
understood, nanotechnology could represent a convenient strategy in addition to other approaches to provide
positive outcomes for COVID-19 treatment.
future science group 10.4155/tde-2020-0069
Commentary Mainardes & Diedrich
Author contributions
RM Mainardes and C Diedrich proposed and structured this article, and they wrote this article together.
Financial & competing interests disclosure
This work was nancially supported by Coordenac¸ ˜
ao de Aperfeic¸ oamento de Pessoal de N´
ıvel Superior - Brazil (CAPES) - Finance
Code 001, and Conselho Nacional de Desenvolvimento Cient´
ıco e Tecnol ´
ogico (CNPq-Brazil – proc 313800/2018-9). The authors
have no other relevant afliations or nancial involvement with any organization or entity with a nancial interest in or nancial
conict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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