Nature-Inspired Alternatives to PEG for Next-Generation Long-Circulating Nanocarriers

Abstract: Polyethylene glycol (PEG) has long been considered as the gold standard for imparting stealth properties to nanocarriers. However, the recent emergence of anti-PEG antibodies has spurred innovation toward nature-inspired alternatives. By mimicking the structural and functional architectures of biological systems such as cell membranes and protein corona, nanocarriers can be engineered to achieve prolonged circulation, superior biocompatibility, and active targeting capabilities. This perspective presents nature-inspired alternatives to PEG, including cell membranes and the protein corona, for extending the circulation time of nanocarriers. It also highlights current challenges associated with these nature-inspired alternatives and outlines future research directions to overcome these hurdles in designing next-generation long-circulating nanocarriers. The infographic explores nature-inspired alternatives to PEG for long-circulating nanocarriers. It includes: 1. Classic PEGylated Nanocarriers: Highlights PEG as the standard stealth coating for decades that prevents immune detection and extends circulation time. 2. Problem: Anti-PEG Antibodies: Demonstrates how these antibodies accelerate clearance and reduce therapeutic efficacy. 3. Bio-Inspired Alternatives: i. Cell Membrane-Coated Nanocarriers: Employ cell membranes to achieve biomimetic stealth, enabling immune evasion, prolonged circulation, improved biocompatibility, and enhanced targeting. ii. Dysopsonin Corona-Coated Nanocarriers: Utilize a dysopsonin corona (e.g., albumin, clusterin) to provide natural stealth by reducing opsonization and extending circulation time. These nature-inspired coatings effectively address the challenges posed by anti-PEG immunity.Nature-inspired alternatives to PEG, tackling anti-PEG antibodies with bio-inspired stealth coatings. Keywords: long circulation, ABC phenomenon, cell membranes, protein corona