Amphiphilic copolymers with precise macromolecular topologies are crucial in nanomedicine for enhancing drug delivery by improving solubilization, stabilization, and therapeutic efficacy on target tissues. This study employs a design-by-architecture approach to identify factors influencing interactions between synthesized macromolecules and biological systems for optimal drug nanodelivery. Copolymers combining poly(ε-caprolactone) blocks and poly(polyethylene glycol methacrylate) or poly(glycerol methacrylate), were synthesized to investigate how architectural adjustments impact self-assembly, nanoparticle size, drug loading, and biomolecule interactions. Linear and brush block copolymers with varied block lengths were studied for their self-assembly behavior in aqueous environments. Both copolymer types formed smaller nanoparticles with extended hydrophilic blocks, with brush block copolymers showing superior performance due to their peculiar macromolecular architecture. Incorporating ‘clickable’ glycidyl units within the hydrophilic block minimally affected particle size. Controlled functionalization with thiol groups resulted in stable nanoparticles with enhanced size reduction and mucoadhesive properties, potentially improving targeted drug delivery and therapeutic effects.
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