Antibody-mediated recognition of chiral poly(2-oxazoline) nanorods driven by enantioselectivity

Chirality critically governs the pharmacodynamics and clinical performance of small molecule drugs, yet its role in governing bio-nano interactions of synthetic polymeric nanocarriers has remained largely unexplored. Surface grafting with hydrophilic, biocompatible "stealth" polymers such as poly(ethylene glycol) (PEG) is a critical design strategy for nanomedicines intended to reduce nonspecific biological interactions and achieve prolonged circulation. However, the rising prevalence of anti-PEG antibodies has driven the search for fundamentally new design principles, mostly focused on substituting PEG with an entirely different polymer type. Poly(2-oxazoline)s (POx) constitute a versatile class of biocompatible synthetic polymers that uniquely enable access to numerous water-soluble macromolecules that can be rendered chiral, an attribute rarely accessible in synthetic stealth polymers. Here, we report the fabrication of crystalline-core nanorods bearing a chiral poly(2,4-dimethyl-2-oxazoline) (PdMeOx) corona via crystallisation-driven self-assembly (CDSA), and examine the influence of polymer chirality on biodistribution and antibody recognition in vivo. Well-defined enantiopure and racemic PdMeOx-b-poly(2-(isopropyl)-2-oxazoline) block copolymers were synthesised and assembled into short nanorods with distinct optical activities, enabling a detailed investigation of chirality-dependent bio-nano interactions. We demonstrate that polymer chirality induces the generation of enantiomer-specific antibodies, an effect that has not previously been reported for synthetic macromolecular nanomaterials. These findings reveal stereochemistry as an orthogonal design parameter for modulating immune interactions and suggest a future strategy in which alternating polymer chirality, rather than changing polymer type, can be exploited to mitigate antibody-mediated clearance through structured dosing regimens.