Challenges and Risks of Nanotechnology in Medicine: An Immunologist's Point of View

Complement Activation: A Potential Threat on the Safety of Poly(ethylene glycol)-Coated Nanomedicines

“…C activation, a known “bridge” between innate and specific immunity, enhances the rise of anti-poly­(ethylene glycol) antibodies (Abs), which bind to the NPs, further enhancing C activation and ABC to close the cycle. Scheme reprinted with permission from ref . Copyright 2017 Wiley.…”

Understanding the Role and Impact of Poly (Ethylene Glycol) (PEG) on Nanoparticle Formulation: Implications for COVID-19 Vaccines

“…Although the mechanism of these rare adverse reactions is still unknown, complement proteins as well as the presence of anti-PEG antibodies are believed to play an important role. These biomolecules are interconnected in what has been identified as the immune stimulatory vicious cycle ( Szebeni, 2016 ), which produces adverse immunological reactions including CARPA. The anaphylactic reactions associated with COVID-19 vaccines are extremely rare and it is still unclear whether PEG molecules are the main culprit.…”

“…Blood analysis collected soon after the administration of Doxil showed fragments from the complement cascade and the complement activation was proposed as a mechanism behind these hypersensitivity reactions ( Chanan-Khan et al, 2003 ; Szebeni et al, 2011 ). These non-IgE-mediated hypersensitivity reactions are known as complement activation-related pseudoallergy (CARPA), with symptoms very similar to the type I hypersensitivity reaction, though they occur upon first contact without prior exposure, and lack a specific allergen, which is why it is called “pseudoallergy” ( Szebeni, 2014 ; Szebeni, 2005 ; Szebeni, 2016 ) ( Figure 5 ). This type of reaction was first described in the 1970s, caused by the radiocontrast agents ( Lang et al, 1976 ; Kolb et al, 1978 ), but it was not until 2001 that it was recognized as a new type of hypersensitivity reaction ( Szebeni, 2005 ).…”

“…Since PEGylated liposomes have been reported to trigger the production of antibodies by B cells without the assistance of T-helper cells ( Ichihara et al, 2011 ; Hou et al, 2021 ), such NPs could potentially act as two different types of antigens, T-independent-1 (TI-1) and T-independent-2 (TI-2) antigens ( Wang et al, 2007 ; Ichihara et al, 2011 ; Szebeni, 2016 ). TI-1 antigens activate B cells in a concentration-dependent manner: at high concentration, the signal is sufficient to induce proliferation and antibody secretion without specific antigen binding to immunoglobulin.…”

“…TI-1 antigens activate B cells in a concentration-dependent manner: at high concentration, the signal is sufficient to induce proliferation and antibody secretion without specific antigen binding to immunoglobulin. At low concentration, only B cells specific for the antigen are able to bind and, therefore, this produces a specific antibody response to epitopes on the antigen ( Murphy et al, 2016 ; Szebeni, 2016 ). On the other hand, TI-2 antigens are molecules with highly repetitive structures and activate mature B cells through the crosslinking of B cell receptors.…”