Bioactive Polysulfate‐Based Nano‐Assemblies Against Virus Infection

3D nanosystems equipped with polysulfates as binding sites are effective virus inhibitors due to their ability to dynamically deform while adhering to a virus. Here, a new supramolecular nanosystem assembled from a block copolymer consisting of sulfated linear polyglycerol and polytrimethylene carbonate is presented. It exhibits a unique morphology, 100 nm sized spheres with a distinct brush-like corona. The negatively charged sulfates are distributed on the outer shell and enable exceptional homogeneity of the particles, thereby enhancing the efficiency of multivalent interactions. Various sulfation levels are tested and demonstrated extremely low half-maximal inhibition concentration (IC₅₀) values in plaque reduction assays tested on herpes simplex virus type-1 (HSV-1): 0.43, 0.16, and 0.037 µg mL^-1 of the 45%, 76% and 100% sulfated assemblies, respectively. Using cryo electron microscopy (cryo-EM), viruses trapped are observed by multiple layers of the nano-assemblies. Both 76% and 100% sulfated assemblies show therapeutic potential in the post-infection model. The inhibitory behavior of the 76% and 100% sulfated assemblies is further confirmed against Omicron infection. This work demonstrates that the presented 3D flexible nano-assemblies can block the virus entry into the host cells with superior morphology and efficiency, establishing them as a promising candidate for antiviral applications.