Nano-materials can be used widely or not, depending mainly on their toxicity [1]. Market consumption of nanomaterials is accelerating. Freedonia Group expected demand for nanomaterials to grow to $100 billion by 2025. However, the uses of nanomaterials in commercial products nowadays increase at a higher speed than the development of research and regulations to prevent their potential toxicity in the manufacture/application/disposal.

 

In general, their potential toxic effects might be contributed not only by the type of base materials, but also by their size/ ligands/surface (chemical) modifications. Regarding the size effect, some studies reported that nanoparticles (<100 nm) might be more toxic than microparticles (>2 µm). These small nanoparticles (<100 nm) were considerably smaller than many cells in the body. Once getting in the body, some kinds of nanoparticles may have the ability to translocate to other organs, depending on their chemical reactivity/surface characteristics/ chemical affinity on body proteins. In addition, cells growing in tissue culture could pick up most nanoparticles. In case of gold, bulk gold has been considered to be “safe” and chemically inert. It was reported that nanogolds (> 5 nm) can be chemically inert like the bulk. However, nanogolds less than 2 nm had chemical reactivity that was different than both organogold complexes and larger nanogolds. Besides, at certain doses, the cationic nanogolds (2 nm) found to be toxic, but these negatively charged nanogolds do not exhibit toxicity (became not toxic) at the same concentration.

 

For bacteria, nanoparticles could attack/kill the bacteria through various processes, such as i) production of reactive oxygen species (ROS); ii) electrostatic interaction with cell membrance; iii) ion releases; and iv) internalization [1].

 

For human, studies on inhaled nanoparticles from air pollution (PM10/PM2.5; combustion/diesel exhaust) indicated that these ultrafine particles/nanoparticles are associated with a wide variety of effects including pulmonary inflammation, immune adjuvant effects [2] and systemic effects including blood coagulation and cardiovascular effects [3]. Besides, when nanoparticles enter systemic circulation they immediately interact with blood cells/proteins/endothelial cells, and components of the coagulation system (platelets/plasma coagulation factors) [4]. These nanoparticles could induce undesirable alterations in the balanced function of these components, then may cause severe and even life-threatening toxicities. Therefore, there are increasing concerns about nanoparticle-induced coagulopathies (i.e., coagulation disorders caused by perturbation of the blood coagulation system), such as the prognosis of cardiovascular diseases due to the induction of thrombotic complications [5–8]. Other toxic risks are the disseminated intravascular coagulation (DIC), consumptive coagulopathy, and deep vein thrombosis (DVT) [9].

As low-dose and multiple drugs, nano-medicines might have many advantages over the conventional medicines, such as improved efficacy, bioavailability, dose–response, targeting ability, and personalization [10].

 

The aims for drugs-loaded nanocontainers/nanocapsules are either enhanced delivery to, or uptake by, target cells and/or a reduction in the toxicity of the free drug to non-target organs. The smart nanocontainers are typically related with the smart releasing property for their embedded drugs. These smart releases could be obtained by using the smart coatings as their outer nanoshells. In this regard, the embedded drugs could be released from nanocontainers by external or internal stimuli, which referred to the chemical/physical/biochemical changes within or surrounding of the nanocontainer [11]. Various types of nanomaterials have been used to fabricate these nanocontainers, such as polymers, lipids, metals... Natural and biodegrable nanomaterials are usually preferred over synthetic nanomaterials [12]. As reported, current nano-medicines used the phenylboronic acid-installed polymeric micelles, matrix metalloproteinase 2-sensitive poly(ethylene glycol)-drug conjugate, multifunctional DNA nanoflowers, single vehicular delivery of small interfering RNA (siRNA), nanoparticle-mediated codelivery of siRNA and prodrug, lipopeptide nanoparticles for siRNA delivery, ferrous iron-dependent drug delivery, polyprodrug amphiphiles, transepithelial transport of Fc-targeted nanoparticles, mutant KRAS target, monovalent molecular shuttle, near-infrared-actuated devices, transferrin receptor trafficking, remote loading of preencapsulated drugs, ATP-mediated liposomal drug delivery, nanoparticle-based combination chemotherapy delivery system, nucleic acid nanoparticle conjugates, ultrasound-triggered disruption of cross-linked hydrogels, refilling drug delivery depots through the blood, siRNA payloads to target KRAS-mutant cancer, delivery of antibody mimics into mammalian cells, biologically “smart” hydrogel, combination of liposomes containing bio-enhancers, and tetraether lipids [12].

 

The main problem in the use of drug-loaded nanoparticles is the entrapment of nanomaterials/nanoparticles in the mononuclear phagocytic system as present in the liver and spleen [13, 14]. For liposomes with sizes >100 nm the clearance rate by the mononuclear phagocytic system increased with increasing size, while for sizes < 100 nm, their charge was more important [15, 16].

 

In addition, nanoparticles have been used for drug delivery to the brain. Nanoparticles (nano-medicines) could get access to the brain by two different pathways: i) transsynaptic transport after inhalation through the olfactory epithelium, and ii) uptake through the blood-brain barrier (BBB) [17]. As report, the brain is a challenging organ for drug delivery, due to the BBB- as the best gatekeeper in the body toward exogenous substances [18]. Passage of the BBB was suggested to be possible by the toxicity of nanoparticles (size of 200 nm) on cerebral endothelial cells [19], but not possible for similar nanoparticles in larger size (~ 300 nm) [20]. Thus, healthy BBB contains defense mechanisms protecting it from blood borne nanoparticle exposure.

As low-dose and multiple vaccines, nano-vaccines might have many advantages over the conventional vaccines. For Covid-19 pandemic, several types of pre-clinical and approved nano-vaccinces have been developed, with the average size of nanoparticles is about 60–100 nm [21].

 

3.1. mRNA-based Covid-19 vaccine

 

Since the mRNA is unstable and very fragile/sensitive, mRNA vaccines must be carefully preserved at very low temperatures [22].

 

-The Pfizer–BioNTech Covid-19 is an mRNA-based Covid-19 vaccine developed by the German biotechnology company BioNTech (mRNA producer) and for its development collaborated with American company Pfizer (medicines and vaccines producer). The vaccine is given by intramuscular injection. It is composed of nucleoside-modified mRNA (modRNA) encoding a mutated form of the full-length spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. The standard dose of Pfizer is 30 micrograms[22].

 

-Moderna vaccine is mRNA vaccine composed of nucleoside-modified mRNA (modRNA) encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles. Each dose of Moderna contains 100 micrograms of a vaccine [22].

 

-CVnCoV (CureVac) is mRNA vaccine is developed in Germany (phase 3) with a lipid nanoparticle-encapsulated mRNA vaccine that encodes full-length, pre-fusion stabilised SARS-CoV-2 spike protein (each dose contains12 micrograms of vaccine) [23].

 

 -Novavax vaccine (NVX-CoV2373) is developed by Novavax and the Coalition for Epidemic Preparedness Innovations. CoV2373 has been described as both a protein subunit vaccine and a virus-like particle vaccine through the producers call it a "recombinant nanoparticle vaccine". The vaccine is produced by creating an engineered baculovirus containing a gene for a modified SARS-CoV-2 spike protein. In phase 1 of the clinical trial, two dose levels of 5 micrograms and 25 micrograms have been evaluated [22].

 

- ARCoV (Walvax) is mRNA vaccine is developed in Mexico (phase 1) with lipid nanoparticle formulation that contains the full spike protein plus CpG7909 to trigger immune response[24]

 

3.2. Other RNA-based vaccines

 

-COVAC1 is self-amplifying RNA vaccine developed in Imperial College (UK, phase 1-2) using cationic liposome formulation containing the spike protein sequence [25].

 

- HDT-301 (HDT Bio) is repRNA vaccine developed in Brasil (phase 1) with lipid inorganic nanoparticle (LION) emulsion containing the viral spike protein sequence [26].

 

- HGC019 (Gennova-HDT) is RNA vaccine developed in India (phase 1-2) with lipid inorganic nanoparticle (LION) emulsion containing the full spike protein plus CpG7909 to trigger immune response [27].

 

-Arct-021 (LUNAR-COV19) by Duke NUS Med School (Singapore) is a self-transcribing and replicating RNA (STARR)-based vaccine (Phase 1-2) with lipid nanoparticle formulation for delivery the spike protein sequence. Single-dose vaccines (2 micrograms or 10 micrograms) have been evaluated [28].

 

3.3. COVID-19 vaccination and neurological effects

 

It was reported in the literature [29] that conventional (intramuscular) vaccines mostly remain near the site of injection (the arm muscle) and local lymph nodes. However, in case of nano-vaccines, as nanoparticles they could enter the systemic circulation/cardiovascular system, then travel to heart/brain/lung and other organs.

 

The main effects of nanoparticles/nanomaterials have been found in the lungs and others inflammation/tissue damage/fibrosis/tumour generation. The cardiovascular system may also be affected [30].

 

Nanoparticles (nanomaterials) are not harmless. They have their own nano-toxicity [1]. Similarity, mRNA is also not fully safe but spike proteins are pathogen.

 

The most frequent neurological side effects of SARS-CoV-2 vaccines are headache, Guillain-Barre syndrome (GBS), venous sinus thrombosis (VST), and transverse myelitis [31, 32]. Patone et al. [33] reported an increased risk of hemorrhagic stroke with Pfizer vaccine. Classen [34] signaled the connection between COVID-19 RNA-based vaccines and the risk of prion disease. Chaurasia et al. [35] reported the cognitive deficits and memory impairments after COVID-19 vaccination (AstraZeneca vaccine).

 

In addition, Guillain-Barre syndrome (GBS) following Pfizer COVID-19 vaccine has been reported [36, 37].

 

3.4. COVID vaccination and blood clots

 

From 8 to 28 days after a first dose of the AstraZeneca vaccine, researchers identified an increased risk of rare blood clotting events and low platelet counts. In the same time period after a first dose of the Pfizer-BioNTech vaccine, the study found the risk of blood clots and strokes caused by restricted blood flow to the brain (ischaemic stroke) increased [38].

 

Chui et al. [39] reported that among 5,526,547 doses of Pfizer and 3,146,741 doses of CoronaVac vaccines were administered, there were 334 and 402 thromboembolic events, and 57 and 49 hemorrhagic stroke cases occurred within 28 days after Pfizer and CoronaVac vaccinations, respectively. The authors also found thrombosis or hemorrhage in the brain or leg were reported with Pfizer-BioNTech vaccine. Other case reports of thrombosis or hemorrhage in the brain or leg were also reported with Pfizer-BioNTech vaccine [40-42].

 

Recently, we proposed the use of artificial bloods for severe Covid-19 patients [43].

 

3.5. COVID vaccination and Myocarditis/Pericarditis

 

Myocarditis is inflammation of the heart muscle, whereas pericarditis is inflammation of the outer lining of the heart. Myocarditis and pericarditis have been reported especially in adolescents and young adult males within several days after mRNA COVID-19 vaccination (Pfizer-BioNTech or Moderna) [44, 45]. In June 2021, the U.S. Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices reported a likely link between mRNA COVID-19 vaccination and myocarditis, particularly in people younger than 39 [46]. In addition, the evidence grows stronger for Covid vaccine link to heart issue [47].

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47. Evidence grows stronger for Covid vaccine link to heart issue, CDC says.