The article describes the interactions between poly (oxonorbornenes) (PONs)-coated gold nanoparticles (AuNPs) with phospholipid vesicles and shows that the strength of these interactions strongly depends on the molecular structure of PONs, specifically their amine/alkyl side chain ratio. PONs, which are a recently introduced class of cationic polyelectrolytes, can be systematically varied to control the amine/alkyl ratio and to explore how the chemical character of cationic polyelectrolytes affects their interactions and the interactions of their nanoparticle conjugates with model membranes. Our study shows that increasing the amine/alkyl ratio by copolymerization of diamine and 1:1 amine/butyl oxonorbornene monomers impacts the availability of PONs amine/ammonium functional groups to interact with phospholipid membranes, the PONs surface coverage on AuNPs, and the membrane disruption activity of free PONs and PONs-AuNPs. The study makes use of transmission electron microscopy, UV-vis spectroscopy, dynamic light scattering, thermogravimetric analysis, fluorescamine assay, ζ-potential measurements, and X-ray photoelectron spectroscopy measurements to characterize the PONs-AuNPs' size, size distribution, aggregation state, surface charge, and PONs surface coverage. The study also makes use of real-time fluorescence measurements of fluorescent liposomes before and during exposure to free PONs and PONs-AuNPs to determine the membrane disruption activity of free PONs and PONs-AuNPs. As commonly observed with cationic polyelectrolytes, both free PONs and PONs-AuNPs display significant membrane disruption activity. Under conditions where the amine/alkyl ratio in PONs maximizes PONs surface coverage, the membrane disruption activity of PONs-AuNPs is about 10-fold higher than the membrane disruption activity of the same free PONs. This is attributed to the increased local concentration of ammonium ions when PONs-AuNPs interact with the liposome membranes. In contrast, the hydrophobicity of amine-rich PONs, which are made for example from diamine oxonorbornene monomers, is significantly reduced. This leads to a significant reduction of PON surface coverage on AuNPs and in turn to a significant decrease in membrane disruption.