Facile Generation of Heterotelechelic Poly(2-Oxazoline)s Towards Accelerated Exploration of Poly(2-Oxazoline)-Based Nanomedicine.

Controlling the end-groups of biocompatible polymers is crucial for enabling polymer-based therapeutics and nanomedicine. Typically, end-group diversification is a challenging and time-consuming endeavor, especially for polymers prepared via ionic polymerization mechanisms with limited functional group tolerance. In this study, we present a facile end-group diversification approach for poly(2-oxazoline)s (POx), enabling quick and reliable production of heterotelechelic polymers to facilitate POxylation. The approach relies on the careful tuning of reaction parameters to establish differential reactivity of a pentafluorobenzyl initiator fragment and the living oxazolinium chain-end, allowing the selective introduction of N-, S-, O-nucleophiles via the termination of the polymerization, and a consecutive nucleophilic para-fluoro substitution. The value of this approach for the accelerated development of nanomedicine is demonstrated through the synthesis of well-defined lipid-polymer conjugates and POx-polypeptide block-copolymers, which are well-suited for drug and gene delivery. Furthermore, we investigated the application of a lipid-POx conjugate for the formulation and delivery of mRNA-loaded lipid nanoparticles for immunization against the SARS-COV-2 virus, underscoring the value of POx as a biocompatible polymer platform.