Toward Hemocompatible Self-assembling Antimicrobial Nanofibers: Understanding the Synergistic Effect of Supramolecular Structure and PEGylation on Hemocompatibility.

A significant challenge associated with systemic delivery of cationic antimicrobial peptides and polymers lies in their limited hemocompatibility toward vast numbers of circulating red blood cells (RBCs). Supramolecular assembly of cationic peptides and polymers can be an effective strategy to develop an array of antimicrobial nanomaterials with tunable material structures, stability and thus optimized bioactivity to overcome some of the existing challenges associated with conventional antimicrobials. In this work, we will demonstrate the supramolecular design of self-assembling antimicrobial nanofibers (SAANs) which have tunable supramolecular nanostructures, stability, internal molecular packing and surface chemistry through self-assembly of designed cationic peptides and peptide-PEG conjuguates. The interaction of the SAANs with human RBCs was evaluated in a stringent biological assay (beyond a traditional hemolysis assay) where both hemolytic and eryptotic activity were examined to establish a fundamental understanding on the correlation between material structure and hemocompatibility. It was found that although the SAANs showed moderate hemolytic activities, their abilities to induce eryptosis vary significantly and are much more sensitive to the internal molecular packing, supramolecular nanostructure and stability of the nanofiber. Improved hemocompatibility requires PEGylation on stable supramolecular nanofibers composed of highly organized β-sheet structure while PEG conjugation on weakly packed nanofibers composed of partially denatured β-sheets did not show improvement. The current study reveals the fundamental mechanism involved in the selective hemocompatibility improvement of the SAANs upon PEG conjugation. The structure-activity relationship developed in this study will provide important guidance for the future design of a broader family of peptide and polymer-based assemblies with optimized antimicrobial activity and hemocompatibility.