Beyond PEG: Re-Engineering Stealth-Polymers to Do More Than Just Hide.

After nearly five decades of clinical dominance, polyethylene glycol (PEG) is approaching an inflection point. Pervasive environmental exposure has driven anti-PEG antibody prevalence above 70% in some adult populations, transforming the once-reliable stealth shield into a source of accelerated blood clearance (ABC), complement activation-related pseudoallergy (CARPA), and unpredictable loss of efficacy - risks brought into sharp focus by the global rollout of PEGylated lipid nanoparticle mRNA vaccines. PEG is thus no longer a passive bystander, and a generation of drug delivery scientists are responding by re-engineering the corona itself. This review reframes stealth not just as bioinert concealment, but rather as an active interface between a nanomedicine and the host: a programmable surface that can hide, sense, switch, deliver, and target. We examine how branched, bottlebrush, and statistical PEG architectures evade pre-existing antibodies while preserving regulatory familiarity; how dePEGylation triggered by tumour pH, redox, enzymatic, and reactive oxygen species (ROS) cues turns stealth into a temporally controlled handoff; how classical alternatives and new functional stealth polymers of zwitterionic, polyglycerol, and polysulfoxide chemistries deliver ultra-long circulation while simultaneously providing immune tolerance, cryo/lyoprotection, or antioxidant defense; how degradable platforms (heparosan, polyphosphoester, hydroxyethyl starch, PASylation, XTEN, EK zwitterionic peptides) reconcile prolonged half-life with clean metabolic exit; and how bio-inspired tropic coatings - hyaluronic acid, phosphocholine, phosphoserine, fucoidan, sialic acid, glucose and mannose glycopolymers - exploit endogenous receptors to reconcile stealth properties with directional targeting.