Thanks to this pandemic we have the bigger chance to acknowledge nanoparticle (NP). NP is a particle with size 1-100 nanometers, smaller than wavelengths of visible light 400-700nm.
One of the function of NP is to deliver drugs. Chen and Konofagou1 revealed that BBB (blood–brain barrier) opening size was smaller than 3 kDa (2.3 nm) at 0.31 MPa, up to 70 kDa (10.2 nm) at 0.51 MPa, and up to 2,000 kDa (54.4 nm) at 0.84 MPa. BBB opening size can be controlled by the acoustic pressure and predicted using cavitation detection. Average size of LNP (lipid nanoparticle)-mRNA is 82-90nm2. By comparing the size of NP and BBB, it is acceptable that NP smaller than 54nm, can cross the BBB (at 0.84 MPa).
The LNPs consist of a mixture of phospholipids, cholesterol, PEGylated lipids, and cationic or ionizable lipids. The phospholipids and cholesterol have structural and stabilizing roles, whereas the PEGylated lipids support prolonged circulation. The cationic/ionizable lipids are included to allow the complexing of the negatively charged mRNA molecules and enable the exit of the mRNA from the endosome to the cytosol for translation3.
There is evidence that LNPs used in many preclinical studies are highly inflammatory (in mice), according to Ndeupen et al. 2021. The team reported that intradermal injection of the LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate.
Ndeupen and the team injected 10 μg of empty LNP formulated in phosphate buffered saline (PBS) or control PBS intradermally into adult mice. The LNP-injected skin samples macroscopically showed signs of intense inflammation, such as redness and swelling. Flow cytometry revealed massive and rapid leukocytic infiltrates dominated by neutrophils that slowly resolved by day 14. Live/dead staining also revealed significant cell death upon LNP injection. LNPs used in preclinical studies promote swift inflammatory responses at the injection site. Intranasal LNP delivery induces robust lung inflammation and animal death4.
NPs (Nanoparticles) can be distributed and can accumulate in different organs such as the liver, spleen, lungs, kidneys, and brain. It depends on their surface area to size ratio. The toxicity of NPs is dependent on their biophysical properties including size, surface area, surface charge and aggregation state.
Some studies using different animal models showed that NPs accumulate in different organs, interact with cellular macromolecules and cause oxidative stress. The mechanisms are generation of reactive oxygen species (ROS), DNA damage, modification of protein structures and functions and disruption of membrane integrity. NP-induced ROS result, in part, from mitochondrial dysfunction and activation of stress-related cell signaling pathways, as well as DNA damage, that results in cell cycle arrest and apoptosis. Titanium dioxide, have been shown to induce the release of nitric acid and glutamic acid in the brains of mice.
PEG (polyethylene glycol)5
Some evidences showed the existance of anti-PEG antibodies (approaching 50%) in healthy human, due to the exposure of PEG additives. Drugs with PEG are being used frequently. PEG is common in personal care, beauty products, and household cleaning products (e.g. soap, sunblock, cosmetics), as well as processed foods. The presence of pre-existing anti-PEG antibodies might trigger further immunogenic responses to PEG when the human receive PEGylated medications.
Accelerated blood clearance (ABC) is a phenomenon of unexpected immune responses against PEG-conjugated nanocarriers. ABC involves the production of antibodies toward nanocarrier components, including PEG, which reduces the safety and effectiveness of encapsulated therapeutic agents. Another immune response is the hypersensitivity or infusion reaction: complement (C) activation-related pseudoallergy (CARPA).