A Non‐Antigenic Randomized Polyethylene Glycol/Poly(2‐Phenyl‐2‐Oxazine)‐Based Drug Delivery Platform

Polyethylene glycol (PEG) plays a central role in nanomedicine, providing essential properties such as the stealth effect. However, the emergence of anti-PEG antibodies (APAs) increasingly undermines these benefits, raising concerns about safety and efficiency. This creates an urgent need for PEG alternatives. Randomized PEG (rPEG) represents a conceptually new strategy that preserves the PEG-like structure and performance while markedly reducing antigenicity. In this work, rPEG is employed as a non-antigenic A-block in ABA-type polymeric micelles (PMs). To enhance drug loading capacity beyond conventional PMs, the hydrophobic middle block is composed of poly(2-phenyl-2-oxazine) (PPheOzi). rPEG is synthesized by anionic ring-opening polymerization, PPheOzi by cationic ring-opening polymerization, and the combined rPEG-b-PPheOzi-b-rPEG triblock copolymers are linked via copper-catalyzed azide-alkyne cycloaddition. The formulations exhibit a distinct correlation between the solubilization of Efavirenz and the systematically varied rPEG composition, ranging from outstanding to moderate micelle drug loading capacities. A fundamental preclinical safety profile was established through investigations in murine fibroblasts and human peripheral blood mononuclear cells (PBMCs). Competitive enzyme-linked immunosorbent assays (ELISA) revealed a pronounced reduction in APA affinity in comparison to PEG. Taken together, the synergistic combination of rPEG and PPheOzi establishes a non-antigenic micellar platform capable of achieving high drug loadings.