The Mystery Of Cationic Nanocarrier Toxicity

With the application of nanotechnology in the field of medicine, lipid- or polymer-based nanocarriers are becoming the mainstream for delivering small-molecule drugs and large molecules, which has increased the effectiveness of drugs and simplified their administration. Nano-scale carriers not only The advantages of nanomaterials, as well as novel properties and functions, such as the ability to interact with complex cell functions in new ways, can create new biomedical applications. In addition, by designing physicochemical properties or surface modification, nanocarriers have multiple potentials for targeted drug delivery to specific sites. Among them, surface charge is one of the important characteristics of nanoparticles. Positively-charged nanocarriers formed from cationic lipids or polymers are most commonly used in gene delivery as non-viral vectors, including cationic liposomes, polyethyleneimine (PEI), chitosan, and the like. Due to the positively charged surface, cationic nanocarriers can simply load and concentrate nucleic acids by interacting with anionic nucleic acid cargo. Compared with viral vectors, cationic nanocarriers also have other advantages, such as simplicity in large-scale production and less stringent vector size restrictions. Although the benefits of nanocarriers in drug delivery have drawn widespread attention, toxicity has been a major obstacle in the application of cationic carriers. As nanocarriers of drug delivery systems (DDS) have been introduced into the human body, their toxicity has caused increasing public health concern.

In research related to the preclinical or clinical use of cationic nanocarriers, researchers have discovered potential adverse effects due to cell and tissue interactions and the immunostimulation of nanocarriers. Even the most widely used liposome complexes are limited due to the occurrence of toxicity such as inflammatory toxicity, liver toxicity, leukopenia, and thrombocytopenia. It has been reported that cationic carriers such as liposomes and PEI accumulate in the lungs immediately after administration. The lung’s inflammatory response is observed after several hours of topical application of the lipid plexus (atomization or intratracheal perfusion).

Further research found that necrosis is one of the factors that cause this inflammatory response. Necrosis is traditionally considered to be the accidental or passive type of cell death caused by non-physiological stress. However, some recent evidence suggests that the execution of necrotic cell death can be regulated by a set of signal transduction pathways. It is assumed that necrotic cells release endogenous molecules. This hypothetical form of damage is called damage-associated molecular patterns (DAMPs). Previous studies have found that mitochondria in the body can function as a major source of DAMP. For example, mitochondrial DNA (mtDNA) has been reported to induce an inflammatory response after injury. It is conceivable that the inflammatory response induced by cationic nanocarriers may be related to cell death and subsequent release of DAMPs, which in turn chemotactic and activate inflammatory cells. To test this concept, the researchers conducted further exploration.

It was found that injection of cationic nanocarriers (including cationic liposomes, PEI, and chitosan) could lead to the rapid appearance of necrotic cells. Treatment with cationic nanocarriers inhibited Na + / K + -ATPase activity in vitro and in vivo, causing intracellular Na + overload with cell death. The ability of cationic nanocarriers to induce cell necrosis depends on their positive surface charge. Further analysis showed that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA can cause severe inflammation in the body, which is mediated by pathways involving TLR9 and MyD88 signaling. therefore. It can be determined that cationic nanocarriers induce acute cell necrosis through the interaction with Na + / K + -ATPase, and subsequent exposure of molecular patterns related to mitochondrial damage is a key event that mediates the inflammatory response.