Cyclic poly(2-methyl-2-oxazine) (c-PMOZI) brush shells on Au nanoparticles (NPs) exhibit enhanced stealth properties toward serum and different cell lines compared to their linear PMOZI (l-PMOZI) counterparts. While selectively recruiting immunoglobulins, c-PMOZI shells reduce overall human serum (HS) protein binding and alter the processing of complement factor 3 (C3) compared to chemically identical linear shells. Polymer cyclization significantly decreases NP uptake by nonphagocytic cells and macrophages in both complement-deficient fetal bovine serum (FBS) and complement-expressing HS, indicating ineffective functional opsonization. Even in serum-free media, c-PMOZI-coated NPs show reduced internalization by macrophages compared to l-PMOZI-coated NPs, suggesting lower opsonin-independent cell surface affinity. This study demonstrates that cyclic PMOZI suppresses interactions of NPs with proteins and cells, highlighting how control over chain topology expands the polymer chemistry toolbox for modulating the behavior of core-shell NPs within physiological environments.