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For respiratory infections treatment and prevention, we analyze for the first time the possibility of providing a broad range medication based on metallic nanoparticles colloids (NpC) delivery by controlled aerosol inhalation. (i) Based on in-vitro data combined with aerosol deposition characteristics in the respiratory system, we calculate the required effective formulations, dosages and delivery parameters for an aerosol inhalation treatment. The goal is to achieve an effective NpC inhibitory concentration (IC) in the target airway surface liquid (ASL); (ii) We evaluate the clinical safety of such dosages, drawing on information from animal testing data and regulatory limits in the USA for such nanoparticles aerosol inhalation safety. Our analysis indicates a wide range of potentially safe and effective dosages that can be clinically explored, targeting the upper respiratory and bronchial tree system. Similar dosages can also provide antibacterial effectiveness for prophylactic treatment in hospital intensive care units to lower the risk of ventilator-associated pneumonia (VAP). Our calculations are phenomenological, independent of mechanisms. Nevertheless, we highlight a mechanism of action by which any suitably designed NpC, with nanoparticles sized 2–10 nm and having a large negative zeta-potential, preferentially bind to viruses with predominantly positively-charged spike proteins. These will be ineffective against viruses with predominantly negatively-charged spike proteins. Accordingly, the popular silver metal base for NpC serves just as a construction ingredient, and other metal or metal-oxides which can serve to construct the noted nanoparticle properties would be similarly effective. We suggest that inhalation delivery of the proposed antiviral formulations could be applied as a first-line intervention while respiratory infections are primarily localized to the upper respiratory system and bronchial tree.
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Medical Hypotheses 159 (2022) 110753
Available online 3 January 2022
0306-9877/© 2022 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
Nanomedicine formulations for respiratory infections by inhalation
delivery: Covid-19 and beyond
Oron Zachar
Yamor Technologies Ltd., 23 Mahane Yosef, Tel Aviv 6515325, Israel
Respiratory infections
For respiratory infections treatment and prevention, we analyze for the rst time the possibility of providing a
broad range medication based on metallic nanoparticles colloids (NpC) delivery by controlled aerosol inhalation.
(i) Based on in-vitro data combined with aerosol deposition characteristics in the respiratory system, we calculate
the required effective formulations, dosages and delivery parameters for an aerosol inhalation treatment. The
goal is to achieve an effective NpC inhibitory concentration (IC) in the target airway surface liquid (ASL); (ii) We
evaluate the clinical safety of such dosages, drawing on information from animal testing data and regulatory
limits in the USA for such nanoparticles aerosol inhalation safety. Our analysis indicates a wide range of
potentially safe and effective dosages that can be clinically explored, targeting the upper respiratory and
bronchial tree system. Similar dosages can also provide antibacterial effectiveness for prophylactic treatment in
hospital intensive care units to lower the risk of ventilator-associated pneumonia (VAP).
Our calculations are phenomenological, independent of mechanisms. Nevertheless, we highlight a mechanism
of action by which any suitably designed NpC, with nanoparticles sized 210 nm and having a large negative
zeta-potential, preferentially bind to viruses with predominantly positively-charged spike proteins. These will be
ineffective against viruses with predominantly negatively-charged spike proteins. Accordingly, the popular silver
metal base for NpC serves just as a construction ingredient, and other metal or metal-oxides which can serve to
construct the noted nanoparticle properties would be similarly effective.
We suggest that inhalation delivery of the proposed antiviral formulations could be applied as a rst-line
intervention while respiratory infections are primarily localized to the upper respiratory system and bronchial
Whether it is the seasonal u, a sore throat, or early-stage Covid-19
symptoms, presently in the 21st century, there is still no home treatment
medication that is easily accessible and available in pharmacies world-
wide. The impact of this sorry state of medicine amounted to a global
disaster under Covid-19. Moreover, even in the absence of novel epi-
demics, each year the morbidity and economic cost of respiratory in-
fections are huge. The typical research tendency in novel
pharmaceuticals is to develop sophisticated, expensive, patent-
protected, highly potent medications for severely ill patients. In
contrast, when it comes to public health and pandemic prevention, it
may be more impactful to develop a broad-range, mild, cheap, and easily
accessible early-stage medications for home treatment, with low risk of
side effects and wide availability potential, to prevent deterioration mild
patients at home to the severe hospitalized state. From the pitiful present
venture point of anti-viral respiratory infections medication, there may
be a benet, humbly and open-mindedly, to revisit some neglected po-
tential options for advancement.
We argue that good candidates for such desired medication can be
found in a well-dened formulation of nanoparticle colloids for inha-
lation delivery. The antibacterial and antiviral potential of nanoparticle
colloids)NpC(has been extensively demonstrated in in-vitro and animal
testing [16]. Anti-microbial applications of NpC for wound care are
approved by the FDA. Unfortunately, a senseless and uncontrolled
alternative medicinepractice of colloidal silver ingestion led the
pharmacological and academic establishment to widely disregard the
potential application of metal-based NpC as antimicrobial agents in
contexts other than wound care. In particular, there has been no
rigorous analysis of the potential use of inhalation-delivered NpC to
prevent or treat respiratory infections.
We substantiate the potential of antimicrobial NpC formulations,
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Received 29 June 2021; Received in revised form 2 November 2021; Accepted 17 November 2021
Medical Hypotheses 159 (2022) 110753
delivered by inhalation, to minimize the aggravation of respiratory
system infections. We evaluate both (A) viral respiratory infections
(including with SARS-CoV-2, the causative agent of COVID-19), and (B)
bacterial infections, particularly ventilator-associated pneumonia (VAP)
in intensive care unit (ICU) patients. Indeed, the most reliable experi-
ence concerning the treatment of respiratory infections has been gained
in the context ICU-acquired VAP [7]. There are unique factors to
consider for optimal treatment of the lungs. These include aerosol
characteristics, breathing patterns, geometrical factors (lung
morphology), disease state, pharmacokinetics (including lung clearance
and mucus transport). Both the total pulmonary drug dose and the
regional deposition distribution of the lung-deposited aerosol are critical
factors for the clinical success of an inhalation therapy [8].
The pathogenesis of respiratory infections begins mildly in the
nasopharynx or upper bronchial tree portions of the respiratory system
[9,10]. Aggravation occurs once the pathogens and associated inam-
mation migrate to lower portions of the respiratory system [11]. Greater
risk and aggravation of the disease state are associated with an increased
microbial load in the upper bronchial tree. Hence, a desirable clinical
endpoint for the proposed inhaled NpC treatment is the inhibition of
microbial load in the upper sections of the bronchial tree. Such an
endpoint implies treatment when most patients are still at home with
mild symptoms.
We lay the groundwork for future clinical evaluations of inhaled NpC
by determining: (i) the NpC material composition required for effective
antiviral activity; (ii) the effective inhibitory concentration (IC) required
in target respiratory tissues; (iii) the dosage required for practical
inhalation delivery of metal-based NpC antiviral and antibacterial for-
mulations, and (iv) the safe dosage range for clinical evaluation.
Conceptual approach
We follow the principles of antibiotics inhalation delivery [7,12], as
illustrated in Fig. 1. To calculate the dose delivered externally with an
aerosol nebulizer, one needs to consider the various losses that occur on
route to the target bronchial tree organ and sensitivity to the aerosol
properties that determine the deposition fraction.
Our dose calculation is based on the following results (each one
derived in dedicated sections):
Nanoparticles: The antiviral potency of metal nanoparticles is highly
size-dependent, with optimal size being in the range of 37 nm.
Polymer capping agents (PVP, PVA) reduce the antiviral effective-
ness of NpC and better be avoided.
Inhibitory concentration (IC): The target organ is the airway surface
liquid (ASL). For antiviral applications, the nanoparticles minimal
microbicidal IC (MMC) is about 10 µg/mL.
Tissue deposition fraction (TDF): During oral breathing of 5 µm
aerosol droplets, NpC deposit onto the pharynx (30%), bronchial tree
(30%), and alveoli (25%).
Inhalation timing losses (ITL): inhalation duration is about a third of
the breathing cycle. Thus, using a continuous aerosol source, the
aerosol uncontrollably cumulates in the oral cavity during 2/3 of the
breathing cycle. Hence, we assume only about 50% of the nebulized
substance is actually inhaled.
The required delivery dose is calculated by cumulating the effects of
each stage between the aerosolizing nebulizer device and nal target
tissue deposition and dilution into the local airway liquid. The mass (µg)
Fig. 1. Mechanisms by which the dose of an antimicrobial agent inserted into a nebulizer differs from the dose delivered to the target airway location (based on [7]),
with a focus on the fraction deposited in the bronchial tree.
Table 1
Dose calculations for aerosol droplets of various sizes to treat different target tissues.
Droplet size
IC In target tissue
MV Mucosal
Volume (mL)
TDF Tissue Deposit
CC Colloid Concentration
Inhaled dose
AD Aerosolized Dose
(i) Bronchial
5 10 1 0.25 50 1 2
(ii) Bronchial
5 40 1 0.25 120 2 4
(iii) Bronchial
3 25 1 0.1 120 2.75 5.5
(iv) Alveoli 3 10 10 0.33 120 2.75 5.5
O. Zachar
Medical Hypotheses 159 (2022) 110753
of nanoparticles deposited to the target organ location (e.g., bronchial
tree) is distributed into a liquid volume comprising the tissue airway
surface liquid (ASL) plus the deposited solution liquid volume. Equation-
(1) delineates the calculation of required NpC aerosolized dose (AD)
volume that needs to be put into the nebulizer device to achieve the
desired NpC inhibitory concentration (IC) in the target organ location:
CC IC)(1)
where AD (in mL) is a function of the target inhibitory concentration (IC,
in µg/mL), mucosal volume (MV, in mL), tissue deposition fraction
(TDF), inhalation time losses fraction (ITL), and colloid concentration
(CC, in µg/mL).
Results and analysis
Table 1 illustrates examples antiviral formulations delivered by the
oral inhalation of aerosol droplets, as calculated from the above
Equation-1. Using a typical continuous nebulizer (ITL =0.5 assumed)
with 5 µm droplets size, a nebulized dose of 4 mL is required to effec-
tively deposit the IC of 40 µg/mL in the bronchial tree. Inhaled antibi-
otics dosages for chronic airway infections are commonly 25 mL [13].
Hence, we expect inhalation of nebulized similar size dosage of antiviral
solutions to be well-tolerated by home users. For preferential deposition
in the alveoli, smaller aerosol droplets of size 3 µm are required (see
discussion in section 3.6.2).
As common in the practice of antibiotic inhalation treatments, a
target IC inhaled antimicrobial dose should be some signicant multiple
of the theoretical minimum IC (MIC) and also the minimum bactericidal
concentration (MBC). Since the antiviral minimum mucrobicidal con-
centration (MMC) for NpC is about 10 µg/mL, a recommended treatment
target IC may be 40 µg/mL, as illustrated in example (ii) in table-1, for
targeting the bronchial tree.
Target IC determination for antiviral applications
Antiviral effect is obtained only by nanoparticle of size <10 nm (see
section 3.2 below). The capping molecule used for the manufacture of
nanoparticle affects antiviral potency. The popular PVP cap appears to
inhibit antiviral effectiveness signicantly. Therefore, in analyzing the
published data, we limit our consideration to experiments involving
nanoparticles of size <15 nm and to non-PVP-stabilized NpC. The
minimum inhibitory concentration (MIC) is one at which occurs tran-
sition from microbial no-growth to growth. The Minimum Microbicidal
Concentration (MMC) is the least amount of antibiotic required to kill a
microbial organism (e.g., a 50% reduction after 1 h incubation), where
always MIC <MMC. In practice, published data is given at a few discrete
concentration points, from which the MIC or MMC needs to be deduced
somehow by interpolation and often not stated by the authors them-
selves (see an example below for the TGEV coronavirus). The evidence
summarized in Table-2 indicates that an IC of at least 10 µg/mL is
desirable at the target respiratory system location. We contend that the
optimal size of nanoparticles for antiviral effectiveness is 37 nm, not
the 10 nm diameter used in all the referenced experiments. Hence, there
is potential for better efcacy and lower MIC if an optimal NpC are used.
Relation to the mechanism of action
Our core calculations are phenomenological, independent of mech-
anisms. Yet, an understanding of mechanisms may guide future treat-
ment optimization and alternatives. There are multiple ways for bacteria
to interact with silver NpC components (both the nanoparticles and Ag
ions), as discussed by others [18]. Viruses are simpler. Based on the
broad-range effectiveness of silver NpC with diverse capping surface
molecules against many different viruses, we argue that the underlying
mechanism of action of NpC on viruses must be non-specic, simple, and
robust. The prominent material properties that affect the NpC antiviral
binding action are the nanoparticle size and surface electric zeta po-
tential, with all remaining aspects of the chemical composition being
secondary. Thus, we estimate that silver is not essential in itself other
than as a manufacturing basis for nanoparticles with appropriate phys-
ical properties. Other NpC with these properties, such as NpC based on
metal-oxides (e.g., zinc oxides, titanium oxides) would be effective as
well (Iron is not recommended, since iron promotes bacterial biolm
Antiviral mechanism of action Nanoparticle size
The importance of nanoparticle size is much greater for antiviral
compared with antibacterial properties, and we contend that this is
related to the mechanism of action. The antiviral effect arises predom-
inantly from attachment of nanoparticles to the virus. We posit that
antiviral effectiveness is limited to nanoparticles of size <10 nm. This
universality arises from the rather uniform geometric scales of respira-
tory infections viruses (e.g., inuenza and coronavirus), all of which
have diameters of about 100 nm, the distance between neighboring
spike glycoproteins being 1020 nm, and glycoprotein length of about
15 nm. Thus, based on geometrical limitations alone, for a nanoparticle
to interact effectively with a glycoprotein site, its diameter must be
around 10 nm or less. Virus functioning becomes disturbed only when
the virus is sufciently covered by attached nanoparticles [19].
Fig. 2. HIV-1 (a/b) with/without NpC treatment. (c) Size distribution of silver nanoparticles bound to HIV-1 collected from all tested preparations seems to peak at a
nanoparticle size of about 4 nm (adapted from [14]).
O. Zachar
Medical Hypotheses 159 (2022) 110753
We nd supporting evidence for the above argument from experi-
ments and direct imaging of nanoparticles binding to human immuno-
deciency virus (HIV) [14], whose size is 120 nm, with ~ 22 nm spacing
between the glycoprotein knobs. Interestingly, the observed sizes of
nanoparticles bound to HIV (see Fig. 2) are exclusively within 110 nm,
with peak virus attachment effectiveness for nanoparticle sizes in the
range of 37 nm. No nanoparticles of diameter greater than 10 nm were
observed to interact with the virus, even though about 40% of the
overall nanoparticle population in the sample was beyond this size range
Consequently, we estimate that experiments in the literature, pre-
dominantly performed with larger NpC, have skewed IC values too high,
since their effectiveness arises wholly from the margins of the distri-
bution of particles with sizes <10 nm. The best we can do, with the
presently available, is to focus on analyzing published data only from
experiments conducted with ~ 10 nm NpC size. However, there is a need
to perform experiments with purposefully produced NpC nanoparticle
sizes peak distribution in the range of 37 nm.
Antiviral mechanism of action The electrostatic potential of nanoparticles
Nanoparticles are composites, having a metal core and an envelope
capping material (Fig. 3). In a liquid environment, nanoparticles have a
surface electric potential, called the zeta potential, the magnitude of
which is dependent on solution pH. For a typical silver NpC, the zeta
potential is negative.
Unlike bacteria, we conjecture that the broad-range antiviral effec-
tiveness of NpC is a consequence of primarily electrostatic interactions.
The spike proteins of many human affecting viruses (including inuenza
and coronaviruses) are positively charged, likely promoting their bind-
ing to the predominantly negative surface charge of the host cell re-
ceptors (such as ACE2) [20]. Correspondingly, the highly negative
surface zeta-potential of the nanoparticles (which is required to keep
them in colloidal form) leads the nanoparticles to bind selectively to the
spike proteins of viruses and thereby neutralize their receptor binding
afnity. Hence, nanoparticles with a zeta potential stronger than 20
mV or 30 mV are preferred. The silver as a particular atom is unim-
portant in itself, other than as a manufacturing method for generating a
stable, charged, composite nanoparticle colloid. It follows that any
colloid of nanoparticles whose size distribution is predominantly in the
210 nm range and that possess a highly negative zeta-potential strength
of more than 20 mV would work as effectively as silver NpC. Corre-
spondingly, viruses whose spike protein binding sites are less positively
charged will be less affected by the NpC.
Generally, the chemistry of solutions is such that the zeta potential
becomes more negative with increasing pH. Changing pH may even
cross the zeta potential between negative and positive values. In
humans, normal pH values of the bronchial tree mucus are in the range
6.99.0 [22]. Therefore, NpC should preferably have a pH of around
77.5 in order that their zeta potential not overly degrade in the mucosal
Coronavirus evidence
Transmissible gastroenteritis virus (TGEV), a porcine coronavirus,
causes very high mortality in piglets. Fig. 4 presents the results of testing
the effect of NpC on coronavirus TGEV [17]. With nanoparticles of non-
optimal size 1020 nm, tested for 1 h incubation, there is a signicant
inhibitory (>50% reduction) effect at a 12.5 µg/mL concentration and
what seems like near static (no growth) at a 3 µg/mL concentration.
Hence we would conclude from this experiment the values of MIC =3
µg/mL , and MMC =12 µg/mL.
Material properties
Distinguishing ionic vs nanoparticle colloids
It is essential to distinguish between ionic solution (recognized by
clear water-like color) and nanoparticle colloids (identied by a visibly
yellow-brownish color). Ionic silver solution consists of positively
charged silver ions dissolved in water, whereas silver NpC consists of
negatively charged nano-sized chunks of elemental silver, size 1100
nm. Both ionic silver and silver NpC manifest antibacterial properties. In
contrast, regarding antiviral properties, it has been argued that colloidal
particles are signicantly more potent than ionic silver [23].
Signicance of selected stabilization coating of the nanoparticles
Prior testing results suggest that the capping agent material can
affect antiviral effectiveness. For example, it appears that PVP-capped
NpC had practically no antiviral effect on the coronavirus TGEV,
whereas a non-PVP NpC exhibited strong antiviral effectiveness [17]. A
similar result was obtained for HIV, where a ten-fold greater
Fig. 3. (a) A silver nanocrystal core, the PVA capping, and a full snapshot of an equilibrated PVA-stabilized nanoparticle in aqueous media [21]. (b) The zeta
potential of a colloidal nanoparticle is the potential (here negative) at the slip plane surface.
Fig. 4. The coronavirus TGEV (MOI 0.5) was incubated with the indicated
concentrations of silver-based nanoparticles (AgNP) at 37
C for 1 h in DMEM.
The AgNP were of size <20 nm (adapted from [17]).
O. Zachar
Medical Hypotheses 159 (2022) 110753
concentration was needed for a PVP-coated NpC sample to achieve the
same antiviral effect as a non-PVP NpC [13]. Overall, it appears that a
thinner capping layer may have a less deleterious effect on antiviral
Anti-bacterial applications
For bacterial infections, the literature suggests the presence of a
poorly differentiated mixed effect arising from both silver ions and
nanoparticles [18]. A major problem in deriving clear numerical con-
clusions from the published literature is that the IC, commonly stated in
weight fraction units (µg/mL), does not take into account the sensitivity
to nanoparticle size. For the same weight fraction (µg/mL) the number
density (N/mL) of smaller nanoparticles is higher than larger nano-
particles. Since higher number density (number of nanoparticles per
volume) increases the probability of nanoparticlepathogen
interactions, we expect smaller nanoparticles to exhibit greater antimi-
crobial effectiveness for same weight fraction (µg/mL) than larger
nanoparticles (as has been manifested experimentally [24]). Confusion
arises from published studies using different-sized nanoparticles from
one another while expressing the results in weight fraction µg/mL. The
variance in the reported outcomes between publications is an artifact of
the different nanoparticle sizes used in the various protocols, obscuring
the consistency of NpC effects. Considering the antibacterial properties
of silver NpC (e.g., on Pseudomonas aeruginosa) [24], the typical IC
values (~7 µg/mL) of small nanoparticles (~7 nm) are similar to those
of the typical antiviral IC, according to our analysis.
Dose calculation
Antimicrobial drugs exhibit concentration-dependent efcacy.
Therefore, ensuring an appropriate concentration in the relevant body
uid is essential. For inhaled antimicrobials, the applicable body uid
for drug concentration purposes is the airway surface liquid (ASL) [12],
also referred to as epithelial lining uid (ELF). The delivered dose is
deposited on and diluted by the ASL. We argue that dosage planning,
correction, and controlled verication can be achieved by examining the
trachea or primary bronchi (G1). Deposition models indicate that the
trachea and G1 bronchi can serve as lower/upper bounds for all of the
concentration estimators for all rst 10 generations of the bronchial tree
(see Fig. 5). Therefore, BAL sampling of tracheal & G1 bronchi NpC
concentration is a well-dened and measurable verication method of
target IC in the whole bronchial tree organ.
Theoretically, to calculate the dose that needs to be deposited to
achieve the target IC requires knowing the volume of the ASL. Unlike the
predictability of blood volume, the ASL volume may have signicant
inter-personal variability. Such variability may result from individual
disease states (e.g., pneumonia, healthy) or lifestyles (e.g., smoking).
The ASL concentration of an individual patient can be veried by
bronchoalveolar lavage (BAL) sampling.
Concentration in airway surface liquid (ASL)
A dose calculation yields a range of possibilities rather than a xed
number. In clinical practice with antibiotics, the indicated dosage for
achieving a signicant inhibitory concentration (IC) is a substantial
Fig. 5. Local concentration of inhaled aerosol in different generations of the
bronchial tree, where the trachea is generation 0. Adapted from [12].
Fig. 6. Deposition fractions in primary respiratory system structures when breathing at rest. Adapted from [25].
O. Zachar
Medical Hypotheses 159 (2022) 110753
multiple of the MIC within wide clinician-determined margins limited
by the bounds of safety. It is common for antibiotics inhalation to target
IC that can be ten times (10x) the MIC. Similar considerations apply to
our nanoparticles dose calculation.
The bronchial trees rst 10 generations surface area is about 1 m
(10,000 cm
). The ASL layer thickness ranges from about 6 µm in the
trachea to 3 µm in the 10th generation of the bronchial tree [12],
amounting to a combined mucosal volume in the top half of the bron-
chial tree to be about 1 mL in a healthy adult. The surface area of the
alveoli is about 100 m
, with mucosal thickness of about 0.07 µm,
resulting in a total ASL volume of 710 mL. Therefore, the more realistic
target treatment is disinfection of the upper bronchial tree at early stages
before the infection spreads deep into the lungs. The disease state
signicantly affects antimicrobial inhalation delivery. Increased mucus
production dilutes the drug concentration in the ASL, compared with
healthy adults. Fortunately, for inhalation of NpC formulations, our
theoretically computed MIC or MMC are more than 40 times smaller
than the estimated safety limit (see section 3.7 below).
Deposition fraction in target tissue
The deposition fraction factor depends on the:
i. Target tissue location: extra-thoracic, trachea-bronchial (TB)
tree, or pulmonary (alveoli)
ii. Mode of inhalation: nasal or oral
iii. Size of the aerosol droplets.
There is a signicant difference in tracheal-bronchial (TB) tree
deposition between nasal and oral breathing (Fig. 6). Peak nasal
breathing TB deposition is only about 10%, whereas oral breathing TB
deposition is about 30%. Hence, we recommend oral inhalation.
Depending on aerosol droplet size, the deposition fraction is different
in each tissue region. As illustrated in Fig. 6: (a) the peak bronchial tree
deposition fraction (of about 30%) is obtained with aerosol droplets of
diameter ~ 6
m, whereas (b) peak alveoli deposition (of about 30%) is
with aerosol droplets of diameter ~ 3
m. For 5 µm droplets, typical in
mass-produced devices presently on the market, the bronchial tree
deposition fraction is ~ 25% and the alveoli deposition fraction is also
~ 25%.
Inhalation timing losses
Inhalation represents only about a third of the duration of a complete
breathing cycle. Consequently, when aerosols are delivered continu-
ously, during 2/3 of the time the aerosol is cumulated in a cloud within
the oral cavity until the next inhalation begins. Hence, we postulate a
lower-bound working assumption that only about 50% of the aero-
solized dose is considered to have been effectively inhaled. This would
be common for home users utilizing standard commercial medicament
aerosol devices available in pharmacies. By contrast, using a breath-
actuated nebulizer would correspondingly lower wastage of silver NcP
colloid, changing the associated dosage instructions.
Lung clearance
The lungs have innate mechanisms to remove deposited particles.
Thus, we need to examine whether the nanoparticles reside long enough
in respiratory system surface tissue to fulll their antiviral potential. For
indicative reference, we consider the behavior of inhaled antibiotics
(tested in ventilated ICU patients) [26,27]. We note that inhalation-
deposited antibiotics reside for an effective peak duration of about
23 h in the lungs. The NpC experimental data we analyzed were
commonly for 1 h treatments (e.g., for the coronavirus presented in
Fig. 4). Hence, experience with inhaled antibiotics suggests that also the
inhaled NpC will be retained in lung surface tissue for long enough to
exhibit antiviral potency.
Clinical safety
Clinical safety evaluations are performed in the context of an esti-
mated treatment dose and schedule. To be specic, we analyze the
example outlined in table-1(ii): 2 mL of NpC with a concentration of 120
g are inhaled (i.e., a dose of 240
g per treatment), taken two times per
day, which amounts to a daily deposition of about 480
g , taken over
ve days (similar to an antibiotics regimen).
The human body has mechanisms for the disposal of silver. The
natural median daily intake of silver from food and drinks has been
reported to be up to 80
g/day [28]. Therefore, our above scenario of a
recommended treatment regimen (deposition of about 480
g) is a sig-
nicant increase over normal daily dietary intake for a short acute
treatment duration of a few days. When addressing safety or toxicity, the
professional guidelines distinguish between acute exposure of <14 days
and prolonged (repeated dose) or chronic exposure of more than 14
days. Only acute (<14 days) exposure is relevant in our context, but we
shall discuss both.
USA occupational guidelines and exposure limits for airborne silver
dust are all dened on a mass basis. The Occupational Safety and Health
Administration (OSHA) in the USA adopted a threshold-limit value time-
weighted average (TLV-TWA) chronic exposure over a 40-hr week of
g/L) of metallic silver dust. Under a regular breathing
rate of 68 L/min, the resulting silver nanoparticle inhalation of 3642
g/h is considered a safe work environment. It amounts to daily, 8 h,
inhaling ~ 300
g of silver nanoparticles on a prolonged routine basis.
Thus, the treatment regimen stipulated here, of 240
g dose given two
times per day, is close to the safety bounds for acceptable chronic intake
in the work environment in the USA.
However, chronic work environment exposure is not the appropriate
context for acute drug toxicity evaluation. We should focus on the
assessment of short-term inhalation. It has been shown that even after
90 days of continuous inhalation exposure to high doses of silver
nanoparticles (total of 1,143
g/day of silver about three times (3x)
our realistic treatment regimen example the accumulated tissue levels
recover to normal within about 12 weeks from the end of treatment
(Fig. 7). This provides a rm indication of the safety and tolerance of
short-term silver NpC inhalation exposure in that it does not lead to any
lasting accumulation in body tissues.
A test closest to our envisioned treatment protocol was performed on
rats for 10 days, 4 h/day, at a concentration of 3,300
using an aerosol of 5 nm silver nanoparticles, resulting in minimal
pulmonary toxicity or inammation [31]. Human breathing at an
average rate of 6 L/min translates to a daily inhaled dosage of silver
nanoparticle aerosol of 4,700
g/day. This study indicates that, for acute
short-term treatment of <10 days, even an inhalation intake of 4,000
Fig. 7. Tissue silver concentrations in female rats exposed to high levels of
AgNP (381
silver nanoparticles of ~ 15 nm diameter, for 6 h/day, which
amounts to an inhalation dosage of 1,143
g/day of silver) in a 90-day inha-
lation study, followed by a 12-week recovery period. Adapted from [29,30].
O. Zachar
Medical Hypotheses 159 (2022) 110753
g/day, which is about 10 times our realistic treatment regimen
example, would induce no adverse reaction or a lasting residue.
Though marred by the charlatan claims of unprofessional alterna-
tive medicineproducts, there is well-established scientic research on
the antibacterial and antiviral properties of silver NpC. However, the
potential applications for respiratory infections treatment have never
been adequately explored. The surveyed literature indicates that silver
nanoparticles colloids (NpC) of diameter 37 nm can be highly effective
in suppressing many viral pathogens at an inhibitory concentration (IC)
of 10 µg/mL (Table 2). For a treatment via inhalation delivery of silver
NpC (Table 1), inhalation of 1 mL of NpC at a concentration of 120
can achieve a signicant IC of 40
g (i.e., 4x of MMC) in the bronchial
tree airway surface liquid (ASL). With common market continuous
nebulizers, one would need to nebulize a dose of 240
g (because of 50%
inhalation time losses). A twice daily treatment protocol corresponds to
a total daily deposition of 240
g. The available safety information in-
dicates that such doses and regimens are well within the safe range and
enable the safe delivery of even ten times (10x) the IC noted in Table 1.
We estimate that these formulations can effectively prevent and treat
any early-stage respiratory viral infection, including infection with
To set the scale of potential benets, we ash out the remarkable
results of an Inuenza H3N2 in-vivo experiment done on mice (one of
the very few in vivo animal experiments in the NpC literature),
comparing the effectiveness of intranasal administration of NpC to that
of Tamiu (Oseltamivir) [15]. Tamiu is claimed to reduce the number
of patients with severe u complications, such as pneumonia (by 44%)
or hospitalization (by 63%). As shown in Fig. 8 below, it appears that
potentially NpC can be as effective as Tamiu. A NpC u treatment, if
effective as in the mice model, could cost <1/10 of Tamiu, with lower
side effects risk, be available essentially OTC (as market availability of
NpC already is) and be manufactured locally in any country. However,
no investment in clinical human trials was ever done to investigate the
possibility. We can only speculate that this is due to conventional
pharma companies lack of nancial incentives to make the required
investment in development and regulatory procedures. One of the main
goals of this paper is to motivate, guide, and advocate for future in-
vestment in the clinical and regulatory development of NpC treatment
For bacterial infections, particularly in the context of preventing
ICU-acquired VAP, the same formulations are expected to be applicable.
An additional risk-reduction benet of silver NpC inhalation treatment
for ventilated patients is the possibility of suppression of biolm for-
mation inside the endotracheal or tracheostomy tube.
This research received no external funding.
Declaration of Competing Interest
The authors declare the following nancial interests/personal re-
lationships which may be considered as potential competing interests:
Yamor Technologies promotes a drug development program based on
the framework presented in this article.
We thank Alex Singer for editorial assistance in the manuscripts
Consent statement/Ethical approval
Not required.
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... The present study on the characteristics of frankincense-mediated AgNPs using XRD, EDAX, FTIR, SEM, TEM and molecular antibacterial assays will help to understand the potential of BW-AgNPs. AgNPs with a small size of less than 30 nm have been reported to be effective against SARS-CoV-2 [30][31][32]. Therefore, the present study is designed to develop small silver nanoparticles with the capped compounds present in frankincense to develop a novel therapeutic product. ...
... Behzad et al. [41] reported that the shape of NPs plays a vital role in the internalization of NPs into target cells. Nanoparticles with charged or hydrophobic surfaces attract complementary proteins and promote phagocytosis in the target cell [31,42]. In the present study, small spherical BW-AgNPs penetrated inside S. mutans cells and inhibited the virulence of genes; therefore, downstream virulence genes were noticed. ...
... The presently synthesized BW-AgNPs also have a size range less than 30 nm. The zeta potential of the NPs and the size of AgNPs are found to influence NP attachment with viral particles [30][31][32]. Therefore, the synthesized compound can also be an antiviral agent. ...
Green synthesized silver nanoparticles (AgNPs) are expected to have rich biomedical applications as an alternative medicine for health care, with the bioactive compounds of plants acting as moderating agents in the synthesis of silver nanoparticles with high therapeutic potential. In this study, frankincense (also known as Al-liban in Arabic), which is a resin obtained from the bark of the tree Boswellia carterii and a traditional alternative medicine, was used as a moderating agent. The synthesized silver nanoparticles [BW-AgNPs] were characterized using UV–vis, EDAX, FT-IR, and SEM analyses. The antimicrobial activities of the synthesized nanoparticles were tested against Streptococcus mutans, Pseudomonas aeruginosa, Enterococcus faecalis, and Candida albicans. Additionally, the anti-S. mutans activities were traced at the molecular level; the impact of the nanoparticles on eight functional genes, brpA, comDE, spaP, smu360, gtfB, gtfCc, gtfDd and gbpB, was probed; and the minimum inhibitory concentration was quantified using microdilution and resazurin staining techniques. The diameter of the zone of inhibition for S. mutans was 22.0 mm at 200 μg/NP treatment, and the SEM study showed that the NPs were irregular to spherical. The size range of the synthesized NPs was 14.19–85.36 nm, with an average of 14.8 ± 0.3 nm based on the TEM study. The FTIR spectra of crude frankincense and frankincense-mediated AgNPs showed peak bands with closely related wavelengths, which indicates that frankincense participates as capping and surface-attached components in the NPs. The NPs showed high antibacterial action against the oral pathogen S. mutans, which causes dental caries. This finding may promote the development of commercial products that incorporate NPs, such as toothpaste and mouth wash. NPs in a size range of less than 30 nm have been reported to easily target SARS-CoV-2; thus, the AgNPs synthesized here with a size range of 14.188–15.202 nm may pave the way for further research.
Plants are a rich source of biologically active compounds such as essential fatty acids, flavonoids, carbohydrates, glycosides, vitamins, essential oils, proteins, and minerals. These compounds show, among others nourishing, soothing, antioxidant, anti-inflammatory, antibacterial, antifungal, and antiviral activities. Of all vitamins, Vitamin D and vitamin C can play a major role in reducing the risk of respiratory infections caused by SARS-Cov-2. Vitamin D supplementation may be a useful risk-reducing agent for SARS-Cov-2. Through several mechanisms, vitamin D can significantly reduce the risk of Plants sources of vitamins against SARS-CoV-2 Chapter | 8 165 infection. Because vitamin D occurs naturally only in a few foods, such as in some fatty fish (mackerel, salmon, sardines), fish liver oils, vitamin D-fed chicken eggs, and mushrooms exposed to sunlight or UV rays, various enrichment attempts should be made for vitamin D fortification.
The SARS-CoV-2 pandemic is currently the most challenging challenge worldwide. To fight it, it is necessary to achieve and maintain good nutritional status. Human nutrition is influenced by factors such as gender, age, health status, lifestyle, medication and supplement intake. Human nutrition has been used as the basis for resistance to stress during the pandemic. Optimal nutrition and nutrient intake affect the immune system, which is why the only balanced way to survive a pandemic is to strengthen the immune system. There is no evidence that dietary supplements can heal the immune system, except for vitamin C, which is one of the better ways to improve human immunity. Good eating practices, proper nutrition, and a healthy lifestyle can ensure the body’s well-being in overcoming the virus.
Devising strategies to synthesize nanoformulations against infectious diseases is an actively growing area of research in recent times. Especially, plant-based nanoformulations against human viral infections have gained more importance due to the superior properties such as low cytotoxicity, biocompatibility, enhanced therapeutic effect, and low side-effects. Considering the pandemic situation due to COVID-19, it is important to revisit the nanoformulations developed using plant systems against wide range of infectious diseases caused by RNA viruses in humans, which could be useful to identify the potential antiviral agents to combat new coronavirus, SARS-CoV-2. This chapter presents a comprehensive overview of the phyto-derived nanoparticles used as antiviral agents against RNA virus known to cause human viral diseases. Also, the possible ways that these nanoparticles could inhibit the replication of SARS-CoV-2 is presented with supporting literature. The recent developments in nanoformulations against COVID-19 are also discussed.
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The whole world is currently facing a global health crisis due to the coronavirus disease (COVID-19) pandemic caused by SARS coronavirus 2, which started in Wuhan City, China, in December 2019. The pandemic has affected 235 countries, areas or territories and infected over 42 million people across the globe as per WHO update on 27 October 2020. More than 1.1 million people have died and the numbers are increasing daily. However, some drugs have been authorized for emergency treatment of patients, medication and vaccines with proven efficacy to prevent and treat the disease is still under various phases of development. The entire world is consistently making efforts to address three major challenges related to COVID-19 including prevention of its spread, prompt and early diagnosis and treatment of patients to save lives. Touted as one of the game-changing technologies of the century, nanotechnology has huge potential to develop solutions against these three major challenges of the disease. Nanotechnology comprises of multidisciplinary prospects encompassing diverse disciplines including medicine, material science, artificial intelligence, environment, virology, physical sciences, chemistry and biology. The numerous challenges can be addressed through the engineering of the various physicochemical properties of materials presents in abundance in nature. Various claims, studies and reports on research and development to combat these challenges associated with COVID-19 have been collectively discussed in this article from the perspectives of nanotechnology.
A novel SARS-like coronavirus (severe acute respiratory syndrome-related coronavirus-2, SARS-CoV-2) outbreak has recently become a worldwide pandemic. Researchers from various disciplinary backgrounds (social to natural science, health and medicine, etc.) have studied different aspects of the pandemic. The current situation has revealed how the ongoing development of nanotechnology and nanomedicine can accelerate the fight against the novel viruses. A comprehensive solution to this and future pandemic outbreaks includes preventing the spread of the virus through anti-viral personal protective equipment (PPE) and anti-viral surfaces, plus efforts to encourage behavior to minimize risks. Studies of previously introduced anti-viral biomaterials and their optimization to fight against SARS-CoV-2 is the foundation of most of the recent progress. The identification of non-symptomatic patients and symptomatic patients is vital. Reviewing published research highlights the pivotal roles of nanotechnology and biomaterials in the development and efficiency of detection techniques, e.g., by applying nanotechnology and nanomedicine as part of the road map in the treatment of coronavirus disease 2019 (COVID-19) patients. In this review, we discuss efforts to deploy nanotechnology, biomaterials, and stem cells in each step of the fight against SARS-CoV-2, which may provide a framework for future efforts in combating global pandemics.
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2019-nCoV, this tiny crowned virus, which was first spread from Wuhan, China, killed thousands of peoples in China, Italy, Iran, and Spain, in a very short period of time. Now, it reaches to most countries all around the world, and thus, it becomes one of the most important threats against all human race. The fact is, the outbreak of this virus showed us, how much our science about the new viruses is weak and insufficient. In the near future, we have to revolutionary increase our knowledge about viruses and controlling those species. Due to the recent reports about the effect of silver nanoparticles (AgNPs) (in vitro and in vivo) on corona virus family especially influenzas, in this study, we have made attempts to take a glance on the effect of AgNPs on the viruses, and ask ourselves "may nano particles inhibit the 2019-nCoV?".
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Objective: Silver nanoparticles (AgNPs) can be difficult or expensive to obtain or synthesize for laboratories in resource-limited facilities. The purpose of this work was to optimize a synthesis method for a fast, facile, and cost-effective synthesis of AgNPs with antimicrobial activity, which can be readily implemented in non-specialized facilities and laboratories. Results: The optimized method uses a rather simple and rapid chemical reduction process that involves the addition of a polyvinylpyrrolidone solution to a warmed silver nitrate solution under constant vigorous stirring, immediately followed by the addition of sodium borohydride. The total synthesis time is less than 15 min. The obtained AgNPs exhibit an aspect ratio close to 1, with an average size of 6.18 ± 5 nm. AgNPs displayed potent antimicrobial activity, with Minimal Inhibitory Concentration values of ≤ 4 µg mL-1 for Staphylococcus aureus and ≤ 2 µg mL-1 for Candida albicans. The resulting method is robust and highly reproducible, as demonstrated by the characterization of AgNPs from different rounds of syntheses and their antimicrobial activity.
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We calculated the regional deposited dose of inhaled particulate matter based on number/mass concentrations in Amman, Jordan. The dose rate was the highest during exercising but was generally lower for females compared to males. The fine particles dose rate was 1010–1011 particles/h (101–102 µg/h). The PM10 dose rate was 49–439 µg/h for males and 36–381 µg/h for females. While resting, the PM10 deposited in the head airways was 67–77% and 8–12% in the tracheobronchial region. When exercising, the head airways received 37–44% of the PM10, whereas the tracheobronchial region received 31–35%. About 8% (exercise) and 14–16% (rest) of the PM2.5 was received in the head airways, whereas the alveolar received 74–76% (exercise) and 54–62% (rest). Extending the results for common exposure scenarios in the city revealed alarming results for service workers and police officers; they might receive 50 µg/h PN2.5 and 220 µg/h PM10 while doing their duty on main roads adjacent to traffic. This is especially critical for a pregnant police officer. Outdoor athletic activities (e.g., jogging along main roads) are associated with high PM2.5 and PM10 dose rates (100 µg/h and ~425 µg/h, respectively).
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Respiratory syncytial virus (RSV) is an important etiological agent of respiratory infection in children for which no specific treatment option is available. The RSV virion contains two surface glycoproteins (F and G) that are vital for the initial phases of infection, making them critical targets for RSV therapeutics. Recent studies have identified the broad-spectrum antiviral properties of silver nanoparticles (AgNPs) against respiratory pathogens, such as adenovirus, parainfluenza, and influenza. AgNPs achieve this by attaching to viral glycoproteins, blocking entry into the host cell. The objective of this study was to evaluate the antiviral and immunomodulatory effects of AgNPs in RSV infection. Herein we demonstrate AgNP-mediated reduction in RSV replication, both in epithelial cell lines and in experimentally infected BALB/c mice. Marked reduction in pro-inflammatory cytokines (i.e., IL-1α, IL-6, TNF-α) and pro-inflammatory chemokines (i.e., CCL2, CCL3, CCL5) was also observed. Conversely, CXCL1, G-CSF, and GM-CSF were increased in RSV-infected mice treated with AgNPs, consistent with an increase of neutrophil recruitment and activation in the lung tissue. Following experimental antibody-dependent depletion of neutrophils, the antiviral effect of AgNPs in mice treated was ablated. To our knowledge, this is the first in vivo report demonstrating antiviral activity of AgNPs during RSV infection.
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Background: Viral and microbial infections constitute one of the most important life-threatening problems. The emergence of new viral and bacterial infectious diseases increases the demand for new therapeutic drugs. Purpose: The objective of this study was to use the aqueous and hexane extracts of Lampranthus coccineus and Malephora lutea F. Aizoaceae for the synthesis of silver nanoparticles, and to investigate its possible antiviral activity. In addition to the investigation of the phytochemical composition of the crude methanolic extracts of the two plants through UPLC-MS metabolomic profiling, and it was followed by molecular docking in order to explore the chemical compounds that might contribute to the antiviral potential. Methods: The formation of SNPs was further confirmed using a transmission electron microscope (TEM), UV-Visible spectroscopy and Fourier transform infrared spectroscopy. The antiviral activity of the synthesized nanoparticles was evaluated using MTT assay against HSV-1, HAV-10 virus and Coxsackie B4 virus. Metabolomics profiling was performed using UPLC-MS and molecular docking was performed via Autodock4 and visualization was done using the Discovery studio. Results: The early signs of SNPs synthesis were detected by a color change from yellow to reddish brown color. The TEM analysis of SNPs showed spherical nanoparticles with mean size ranges between 10.12 nm to 27.89 nm, and 8.91 nm 14.48 nm for Lampranthus coccineus and Malephora lutea aqueous and hexane extracts respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 417 nm.The green synthesized SNPs of L. coccineus and M. lutea showed remarkable antiviral activity against HSV-1, HAV-10, and CoxB4 virus. Metabolomics profiling of the methanolic extract of L. coccineus and M. lutea resulted in identifying 12 compounds. The docking study predicted the patterns of interactions between the compounds of L. coccineus and M. lutea with herpes simplex thymidine kinase, hepatitis A 3c proteinase, and Coxsackievirus B4 3c protease, which was similar to those of the co-crystal inhibitors and this can provide a supposed explanation for the antiviral activity of the aqueous and nano extracts of L. coccineus and M. lutea. Conclusion: These results highlight that SNPs of L. coccineus and M. lutea could have antiviral activity against HSV-1, HAV-10, and CoxB4 virus.
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Silver is easily available and is known to have microbicidal effect; moreover, it does not impose any adverse effects on the human body. The microbicidal effect is mainly due to silver ions, which have a wide antibacterial spectrum. Furthermore, the development of multidrug-resistant bacteria, as in the case of antibiotics, is less likely. Silver ions bind to halide ions, such as chloride, and precipitate; therefore, when used directly, their microbicidal activity is shortened. To overcome this issue, silver nanoparticles (Ag NPs) have been recently synthesized and frequently used as microbicidal agents that release silver ions from particle surface. Depending on the specific surface area of the nanoparticles, silver ions are released with high efficiency. In addition to their bactericidal activity, small Ag NPs (<10 nm in diameter) affect viruses although the microbicidal effect of silver mass is weak. Because of their characteristics, Ag NPs are useful countermeasures against infectious diseases, which constitute a major issue in the medical field. Thus, medical tools coated with Ag NPs are being developed. This review outlines the synthesis and utilization of Ag NPs in the medical field, focusing on environment-friendly synthesis and the suppression of infections in healthcare workers (HCWs).
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Infectious diseases can be transmitted and they cause a significant burden on public health globally. They are the greatest world killers and it is estimated that they are responsible for the demise of over 17 million people annually. The impact of these diseases is greater in the developing countries. People with compromised immune systems and children are the most affected. Infectious diseases may be caused by bacteria, viruses, and protozoa. The treatment of infectious diseases is hampered by simultaneous resistance to multiple drugs, indicating that there is a serious and pressing need to develop new therapeutics that can overcome drug resistance. This review will focus on the recent reports of metal-based nanoparticles that are potential therapeutics for the treatment of infectious diseases and their biological efficacy (in vitro and in vivo).
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Multidrug resistance of the pathogenic microorganisms to the antimicrobial drugs has become a major impediment toward successful diagnosis and management of infectious diseases. Recent advancements in nanotechnology-based medicines have opened new horizons for combating multidrug resistance in microorganisms. In particular, the use of silver nanoparticles (AgNPs) as a potent antibacterial agent has received much attention. The most critical physico-chemical parameters that affect the antimicrobial potential of AgNPs include size, shape, surface charge, concentration and colloidal state. AgNPs exhibits their antimicrobial potential through multifaceted mechanisms. AgNPs adhesion to microbial cells, penetration inside the cells, ROS and free radical generation, and modulation of microbial signal transduction pathways have been recognized as the most prominent modes of antimicrobial action. On the other side, AgNPs exposure to human cells induces cytotoxicity, genotoxicity, and inflammatory response in human cells in a cell-type dependent manner. This has raised concerns regarding use of AgNPs in therapeutics and drug delivery. We have summarized the emerging endeavors that address current challenges in relation to safe use of AgNPs in therapeutics and drug delivery platforms. Based on research done so far, we believe that AgNPs can be engineered so as to increase their efficacy, stability, specificity, biosafety and biocompatibility. In this regard, three perspectives research directions have been suggested that include (1) synthesizing AgNPs with controlled physico-chemical properties, (2) examining microbial development of resistance toward AgNPs, and (3) ascertaining the susceptibility of cytoxicity, genotoxicity, and inflammatory response to human cells upon AgNPs exposure.
Chemical modification of silver nanoparticles (AgNPs) with a stabilizing agent, such as poly(vinyl alcohol) (PVA), plays an important role in shape-controlled seeded-growth and colloidal stability. However, theoretical aspects of the stabilizing mechanism of PVA are still poorly understood. To gain a better understanding of the role of PVA in water protecting effects for silver nanoparticles, we developed an atomistic model of a AgNP grafted with single-chain PVA of various lengths. Our model, designed for classical molecular dynamics (MD) simulations, approximates the AgNP as a quasi-spherical silver nanocrystal with 3.9 nm diameter and uses a united-atom representation for PVA with its polymer chain length varying from 220 up to 1540 repeating units. We found that PVA adsorbs onto the AgNP surface through multiple non-covalent interactions, among which non-covalent bonding of the hydroxyl groups plays a key role. The analysis of adsorption isotherms by using the Hill, Scatchard, and McGhee & von Hippel models exhibits evidence for positive binding cooperativity with the cooperativity parameter varying from 1.55 to 2.12. Our results indicate that the size of the PVA polymer rather than its structure plays a crucial role in providing water protecting effects for the AgNP core, varying from 40% up to 91%. The water-protecting efficiency was well approximated by the Langmuir–Freundlich equation, allowing us to predict that the saturated coverage of the nanoparticle of a given diameter of 3.9 nm should occur when the PVA molecular weight approaches 115 kDa, which corresponds to the number of vinyl alcohol monomers being equal to 3100 units.