Engineering Injectable Hydrogels from Lipoic Acid-Functionalized Polymer Micelles

Nanoparticle-based drug delivery offers versatile cargo encapsulation and transport, yet maintaining nanocarriers at local administration sites remains challenging.Here, we establish a dithiolane-mediated nanoparticle-to-hydrogel strategy that directly interconnects functional polymer micelles into injectable depots.Amphiphilic triblock copolymers comprising a poly(εcaprolactone) (PCL) midblock and lipoic acid (LA)-functionalized PEGMA-based end blocks self-assemble into micelles with drug-retention domains and crosslinkable coronas.Photoinitiator-free UV irradiation produces disulfide-linked intermicellar networks, with LA content regulating hydrogel mechanics and network lifetime.Micellar organization provides additional mechanical reinforcement and recovery, while the preformed hydrogels exhibit shear-thinning and practical injectability.The macroscopic hydrogel depot can limit immediate nanoparticle dilution and wash-out, while PCL-rich domains and the crosslinked network act together to sustain hydrophobic drug retention.Under glutathione (GSH)-mediated reducing conditions, disulfide cleavage progressively disrupts network connectivity and yields dispersed nanoscale assemblies, demonstrating a reduction-responsive pathway for regulating hydrogel lifetime.Together with favorable cytocompatibility, these findings establish a versatile injectable hydrogel platform integrating tunable mechanics, sustained drug retention, and controlled network disassembly.More broadly, this dithiolane-mediated strategy establishes a modular foundation of cytocompatible, mechanically adaptable, nanoparticle-interconnected hydrogels with potential applications as cell-culture substrates, three-dimensional culture matrices, injectable cell-delivery materials, and materials for extrusion-based biofabrication.