A Topological Trade-Off: Cyclic Poly(2-methyl-2-oxazoline) Shells Enhance Opsonization and Macrophage Uptake of Nanoparticles Despite Superior Protein Repellent Properties

Organically modified silica (ORMOSIL) nanoparticles functionalized with linear poly(2-methyl-2-oxazoline) (L-PMOXA NPs) promote C3b/iC3b-mediated uptake by human myeloid leukocytes in human serum. We tested if NPs functionalized with cyclic PMOXA (C-PMOXA NPs) prevent this effect. The adsorption of human and pig serum proteins to C-PMOXA NPs was reduced compared to L-PMOXA NPs. However, C-PMOXA NPs bound IgG3, IgG1, and complement factors C1q, properdin, and CFAB and activated complement more than L-PMOXA NPs. Consistently, monocytes and macrophages captured C-PMOXA NPs more efficiently than L-PMOXA NPs, while lymphocytes exhibited markedly lower binding of NPs independently of their polymer shells. Despite superior protein repellent properties, cyclic PMOXA shells promote the recruitment of immune agonists and enhance NP opsonization. These limitations may represent a biological bottleneck in designing improved stealth NPs based on the topological modulations of their polymer shells.