Cationic Peptide Antigen Design Dictates Electrostatic Interactions and Immune Signaling in Self-Assembled Immunotherapy Complexes

Designing effective immunotherapies requires a deep understanding of how biophysical cues influence immune responses. Current approaches often lack granular insight into the molecular interactions governing self-assembly of therapeutic complexes. This study addresses this gap by investigating how the design of cationic peptide antigens, when combined with anionic nucleic acid-based modulatory cues, impacts their self-assembly and subsequent immune signaling. Understanding these connections is crucial for rationally tuning immune outcomes for various disease targets.

Researchers designed self-assembled therapeutic complexes using cationic peptide antigens and anionic, nucleic acid-based modulatory cues. They employed temperature replica exchange molecular dynamics to compare molecular contacts, including hydrogen bonding and salt bridges, across a library of peptide sequences. Surface plasmon resonance (SPR) studies quantified binding affinity of these self-assembled immune cues. Finally, in vitro primary cell studies assessed immune signaling, investigating the impact of peptide design on these immunological outcomes.

Peptides with higher cationic charge and those anchored with arginine residues formed more electrostatic interactions during self-assembly compared to peptides with lower cationic charge and lysine residues. Surface plasmon resonance studies further demonstrated that both the type of anchored amino acid residue and the distribution of charge across the peptide significantly influenced the binding affinity of the self-assembled immune cues. In vitro primary cell studies corroborated these findings, showing that immune signaling was likewise sensitive to the total charge, charge distribution, and the specific type of anchored amino acid residues within the therapeutic complexes. These molecular insights provide a foundational understanding of how peptide design directly modulates the biophysical properties and immunological outcomes of these self-assembling systems.

Peptides with higher cationic charge and those anchored with arginine residues formed more electrostatic interactions during self-assembly compared to peptides with lower cationic charge and lysine residues.