Amphiphilic block copolymer conjugated with cell-penetrating-peptides derived from Influenza A H1N1 virus as a biocompatible scaffold for enhanced cell-uptake

Decorating an amphiphilic copolymer with the cell-penetrating peptide of Influenza A H1N1 spike protein harnesses the uptake efficacy of viruses on a simple and modulable scaffold. The bioconjugate showed enhanced uptake and high biocompatibility. • An amphiphilic block copolymer based on glycerol methacrylate were synthesized via RAFT polymerization. • Peptides derived from the spike protein of Influenza A H1N1 were grafted on the amphiphilic block copolymer to develop bioconjugates with enhanced cell penetration properties. • Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) investigations showed that the bioconjugates self-assemble into nanoparticles in aqueous media. • The bioconjugates demonstrated biocompatibility on multiple cell lines. • Preliminary experiments demonstrated that one of the proposed bioconjugates enhanced cell penetration due to the peptide decoration. Amphiphilic copolymers prepared by reversible addition-fragmentation chain-transfer (RAFT) polymerization are versatile and biocompatible scaffolds for multiple drug delivery applications. Decorating these structures with biomolecules and targeting moieties is a proven approach to enhance the cell uptake of polymers. In particular, spike proteins on the surface of the influenza A H1N1 virus are biomacromolecules highly evolved to promote cell adhesion and uptake, leading to effective cell-penetrating processes. We harnessed this uptake ability by selecting the peptide sequences responsible for the cell uptake and grafting them on a methacrylate copolymer. The adopted polymeric scaffold included glycerol, butyl, and N-hydroxy succinimide ester (NHS-ester) groups. This polymer resulted in a water-soluble and biocompatible structure. Moreover, the reactivity of NHS-ester units enabled the modular insertion of the peptide in post-polymerization reactions. Through this approach, we combined the cell penetration efficiency of influenza A H1N1 virus with the easy manipulation of polymers and small biomolecules. The resulting bioconjugate was demonstrated to be a modular, safe, and effective platform for potential intracellular delivery applications.