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Attaching polyethylene glycol (PEG) to proteins, known as PEGylation, remains thus far the gold standard and mostly established approach of stealth coating. As of today, 12 PEGylated proteins have been brought to market, including PEG-asparaginase (Oncaspar®), PEG-adenosine deaminase (Adagen®) and PEG-Intron® 48. In the beginning, random PEGylation method was adopted through reacting the ?-amino group of lysine residues, yet the resultant isomer mixtures were of high heterogeneity that complicated the subsequent purification steps 49. To circumvent this limitation, site-specific amino PEGylation approaches were developed to selectively react the N-terminal ?-amino groups, the carboxyl groups or the cysteines residues to yield more defined conjugating structures  50 51.

The antifouling feature of PEGylated proteins is still not fully understood and considered to arise from the efficacious hydrated layers created by PEG chains, which extensively bond with surrounding water molecules through hydrogen bonding in aqueous solution. Such hydrated layer sterically shields blood serum proteins from approaching, endowing the internal protein core with improved bioavailability, pK behavior, and MPS-avoidance features 52. It is important to note that the characteristics of this hydration layer such as thickness, surface density, and conformation play a dominant role for effective blocking or repulsion of opsonins 40. Specifically speaking, low PEG coverage or surface density may leave unprotected patches in the PEG hydrated layer where opsonin proteins can freely bind with surface epitopes 53; Also, long chain or branched PEG polymer decorated nanoparticles manifests longer blood circulation half-lives than short chain or linear PEG polymer does 54; For final biodistribution, PEGylated nanoparticles preferentially concentrated in the spleen than normally in both the liver and spleen by uncovered nanoparticles 55.

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Though basic designing guidelines can be followed to make PEGylated products, there are still a large number of conflicting results reported, implying the lack of a comprehensive study of the antifouling mechanism and impact factors 56. Additionally, the desire to make longer chain length and higher density of PEG polymers to increase body-residence time of nanoparticles is frequently compromised by decreased protein activity, and the inadequate PEG anchoring may, in turn, amplify the immunogenicity of conjugated polymers 36. Besides, several studies have discovered anti-PEG antibodies in patients after treatment with PEGylated therapies 57 58. Therefore, developing substitute stealth coatings that can further evade the immune system is urgently needed but challenging.

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