Unimolecular chiral poly(amino acid)s as adjuvants of nanovaccines for augmented cancer immunotherapy

Chirality is pervasive and plays a crucial role in biological processes. Although amino acids possess inherent chirality, the stereochemical influence of this property on the regulation of immune cells remains insufficiently explored. To address this, the unimolecular chiral poly(amino acid)s were synthesized to evaluate their immunostimulatory effects and anti-cancer potential. Among the candidates, G0-P_D-Lys₅₀ emerged as the most effective adjuvant through in vitro screening. When complexed with antigen ovalbumin (OVA) to form chiral nanovaccines, G0-P_L-Lys₅₀-OVA and G0-P_D-Lys₅₀-OVA exhibited similar morphology, particle size, and zeta potential. Despite these comparable physicochemical properties, G0-P_D-Lys₅₀-OVA induced significantly stronger activation of dendritic cells (DCs). Specifically, it resulted in 1.38 and 1.34-fold increases in CD11c⁺CD80⁺ DCs and CD11c⁺SIINFEKL-H-2Kb⁺ DCs in lymph nodes, respectively. In the LLC-OVA cancer model, G0-P_D-Lys₅₀-OVA reduced tumor volume by 50 % compared to its enantiomer. These results establish a unique approach to designing chiral nanovaccines and provide a foundational strategy for developing broadly applicable immunotherapies.