Glycopolymer-based nanofibers with tunable polyelectrolyte content for modulating cellular interactions and drug...

Polymer-based nanoparticles are emerging as a promising class of nanomedicines, yet are typically limited to spherical morphologies with limited control over particle size. As nanoparticle morphology, size, dispersity and surface chemistry dictate their biological performance, developing nanoparticles with precise control over these parameters is essential for the design of next-generation nanomedicines. Here, we report one-dimensional triblock nanofibers with a dual-functional corona, that combine the minimal cytotoxicity of a polyfructose glycopolymer and the improved cellular interaction of polyamine polyelectrolytes. Living crystallization-driven self-assembly enables precise length and dispersity control of poly(fluorene trimethylene carbonate)-b-polyfructose nanofibers from 46 nm to 1.15 µm, with excellent long-term colloidal stability in water. These nanoparticles were then loaded with the anticancer drug paclitaxel, and its delivery to MDA-MB-231 breast cancer cells was investigated. IC₅₀ values as low as 0.038 µg mL^-1 were measured, outperforming free paclitaxel. Flow cytometry and confocal laser scanning microscopy revealed cellular internalization of all crystalline triblock nanofibers by breast cancer cells. Nanofibers with solely amine-based coronas showed superior cellular uptake with low lysosomal accumulation but heightened cytotoxicity, whereas bifunctional nanofibers containing a central polyfructose segment undergo cellular uptake with moderate lysosomal accumulation and minimal cytotoxicity. These results highlight that the precise control over size, sequence and surface chemistry imparted by living CDSA permits systematic tuning of the biological performance of nanoparticles, establishing crystalline triblock nanofibers as a platform for the future design of drug delivery systems.