Titrating Polyarginine into Nanofibers Enhances Cyclic-Dinucleotide Adjuvanticity <i>in Vitro</i> and after Sublingual Immunization.

TitleTitrating Polyarginine into Nanofibers Enhances Cyclic-Dinucleotide Adjuvanticity in Vitro and after Sublingual Immunization.
Publication TypeJournal Article
Year of Publication2021
AuthorsSH Kelly, BJ Cossette, AK Varadhan, Y Wu, and JH Collier
JournalAcs Biomaterials Science & Engineering
Start Page1876
Pagination1876 - 1888
Date Published05/2021

Effective sublingual peptide immunization requires overcoming challenges of both delivery and immunogenicity. Mucosal adjuvants, such as cyclic-dinucleotides (CDN), can promote sublingual immune responses but must be codelivered with the antigen to the epithelium for maximum effect. We designed peptide-polymer nanofibers (PEG-Q11) displaying nona-arginine (R9) at a high density to promote complexation with CDNs <i>via</i> bidentate hydrogen-bonding with arginine side chains. We coassembled PEG-Q11 and PEG-Q11R9 peptides to titrate the concentration of R9 within nanofibers. <i>In vitro</i>, PEG-Q11R9 fibers and cyclic-di-GMP or cyclic-di-AMP adjuvants had a synergistic effect on enhancing dendritic cell activation that was STING-dependent and increased monotonically with increasing R9 concentration. The polyvalent display of R9 on assembled nanofibers was significantly more effective at promoting CDN-mediated DC activation <i>in vitro</i> than mixing nanofibers with an equimolar concentration of unassembled R9 peptide. The sublingual administration of nanofibers revealed a bell-shaped trend between increasing R9 concentration and enhancements to antigen trafficking and the activation of DCs in the draining lymph nodes. Intermediate levels of R9 within sublingually administered PEG-Q11 fibers were optimal for immunization, suggesting a balance between polyarginine's ability to sequester CDNs along the nanofiber and its potentially detrimental mucoadhesive interactions. These findings present a potentially generalizable biomaterial strategy for enhancing the potency of CDN adjuvants and reveal important design considerations for the nascent field of sublingual biomaterial immunization.

Short TitleAcs Biomaterials Science & Engineering