The Topology\nof Poly(2-methyl-2-oxazine) Shells on\nNanoparticles Determines Their Interaction with Serum and Uptake by\nImmune Cells

Cyclic\npoly(2-methyl-2-oxazine) (<i>c</i>-PMOZI)\nbrush\nshells on Au nanoparticles (NPs) exhibit enhanced stealth properties\ntoward serum and different cell lines compared to their linear PMOZI\n(<i>l</i>-PMOZI) counterparts. While selectively recruiting\nimmunoglobulins, <i>c</i>-PMOZI shells reduce overall human\nserum (HS) protein binding and alter the processing of complement\nfactor 3 (C3) compared to chemically identical linear shells. Polymer\ncyclization significantly decreases NP uptake by nonphagocytic cells\nand macrophages in both complement-deficient fetal bovine serum (FBS)\nand complement-expressing HS, indicating ineffective functional opsonization.\nEven in serum-free media, <i>c</i>-PMOZI-coated NPs show\nreduced internalization by macrophages compared to <i>l</i>-PMOZI-coated NPs, suggesting lower opsonin-independent cell surface\naffinity. This study demonstrates that cyclic PMOZI suppresses interactions\nof NPs with proteins and cells, highlighting how control over chain\ntopology expands the polymer chemistry toolbox for modulating the\nbehavior of core–shell NPs within physiological environments.