Fructose‐Based Single‐Chain Polymer Nanoparticles for GLUT1–Mediated Delivery: Impact of Polymer Design on Uptake and In Vivo Performance

We introduce the preparation and biological evaluation of head‐tail, tadpole‐like, single‐chain nanoparticle (SCNP). These libraries are designed to study the influence of block arrangement on cellular uptake and biodistribution. In the first library, PEG‐NPs consisted of a PEG‐based crosslinked head with a fructose‐containing glycopolymer tail (PEG‐head), while the design was reversed in the second library (Fru‐head). Cellular uptake studies revealed significantly higher uptake of NPs with Fru‐head compared to NPs with PEG head, which is attributed to the surface accessibility of the fructose units to glucose transporters (GLUT). In contrast, the fructose moieties in PEG‐NPs are more likely to be embedded within the core of the PEG head, thereby limiting receptor interaction. Additionally, uptake selectivity followed the order MDA‐MB‐231 > MCF‐7 > RAW 264.7, correlating with GLUT expression levels. Mechanistic studies showed that uptake is strongly suppressed by GLUT1 inhibition but surprisingly unaffected by GLUT5 inhibition, a finding attributed to the pyranose structure of fructose. Fru‐head tadpoles showed prolonged blood circulation and reduced clearance in vivo, with a mean residence time (MRD) of around 21 h, depending on the length of the PEG tail.