LAUSR

Chirality is ubiquitous in biological systems, which is closely related to biological functions, life processes, and even the pathogenesis of diseases. However, the interface between the chirality of synthetic materials and organisms, particularly the immune system, remains poorly understood. Here, supramolecular chiral polymer micelles (SCPMs) are prepared by complexing antigenic proteins with chiral amino acid‐modified polyethyleneimine. The introduction of chirality not only reduces the toxicity of cationic polymer, but also benefits cell uptake and antigen presentation. Especially, D‐chirality presents the lowest cytotoxicity, while promoting the highest expression level of costimulatory molecules on dendritic cells compared to L‐chirality and achirality. The superiority of D‐chirality to stimulate dendritic cell maturation is supported by immunization with D‐SCPMs, which achieves significant antigen‐specific proliferation of T cells in the spleen, lymph nodes, and tumor of mice. Chirality‐mediated antigen processing and presentation are demonstrated by D‐SCPMs self‐assembled from chiral alkaline histidine or neutral phenylalanine modified polyethyleneimine and tumor associated ovalbumin or severe acute respiratory syndrome coronavirus 2 spike 1 antigenic protein. Immunoactivation enabled by D‐chirality opens a window to prepare potent nanotherapeutics for disease prevention and treatment.