Antioxidant glycopolymersomes with dynamic covalent glucose regulation for synergistic pancreatitis-diabetes therapy

Abstract

Pancreatitis and diabetes mellitus are interconnected pathologies lacking integrated therapeutic strategies. Current insulin-based therapies risk exacerbating pancreatic inflammation, necessitating "drug-free" alternatives. Herein, we report the first dynamic covalent glycopolymersome platform engineered via reversible addition-fragmentation chain-transfer (RAFT) polymerization and macromolecular self-assembly to synergistically address both conditions. The glycopolymersomes, self-assembled from a triblock copolymer poly(ethylene oxide)-block-poly(4-acrylamidophenylboronic acid-stat-N-acryloyl glucosamine)-block-poly(aminoethyl methacrylate) [PEO-b-P(AAPBA-stat-AGA)-b-PAEMA], integrate glucose-responsive phenylboronic acid moieties for sustained blood glucose regulation and conjugated antioxidants (ferulic acid or tyrosine) for reactive oxygen species (ROS) scavenging. In vitro studies demonstrate reversible glucose responsiveness and potent ROS elimination. In vivo, these glycopolymersomes achieve 60 h of normoglycemia in type 1 diabetic mice and accumulate selectively in the pancreas, mitigating oxidative stress, inflammation, and edema in murine models. Overall, this work pioneers the use of dynamic covalent polymer architectures for dual metabolic regulation, offering a blueprint for insulin-free nanomedicine aimed at treating complex metabolic disorders.