Tailoring Physicochemical Properties of Linear Copolymers for Enhanced Endocytic Uptake

The design of polymeric materials with well-defined, tunable properties is essential for advancing drug delivery systems and other biomedical applications. Optimizing key parameters such as size, surface charge, and temperature responsiveness can enhance targeted drug delivery efficiency and biocompatibility. In this study, we synthesized a series of fluorescently labeled polymers with varying molecular weights and charges via reversible addition-fragmentation chain transfer (RAFT) polymerization to investigate their role in cellular uptake. Comprehensive characterization confirmed that these polymers exhibited precise size and charge distributions, enabling controlled interactions with biological systems. Cellular uptake studies in HeLa cells revealed a strong dependence on polymer size, charge, and temperature, with smaller and positively charged polymers demonstrating superior internalization under physiological conditions (37°C). Further analysis showed that the polymers predominantly localized in endosomes and lysosomes, indicating endocytosis as the primary internalization pathway across different polymer charge types. Overall, these findings provide preliminary insights into how polymer physicochemical properties modulate cellular uptake, which may inform the design of future polymer-based drug delivery systems.