Nanostructured Lipid Carriers Overcome the Low Immunogenicity of M2e Peptide via Surface Click Chemistry Conjugation, Improving the Anti‐M2e Antibody Response

Influenza vaccines targeting hemagglutinin require annual updates due to viral variability, limiting protection against pandemic strains. The conserved matrix protein 2 ectodomain (M2e) peptide offers cross‐strain immunity but suffers from low immunogenicity. Here, M2e peptides are conjugated onto nanostructured lipid carriers (NLCs) using bioorthogonal click chemistry, preserving key epitopes and enhancing antigen presentation. Immunization in mice demonstrates that NLC‐M2e induces focused and robust anti‐M2e antibody responses, which are significantly amplified by incorporating a pan‐DR epitope helper T cell epitope, achieving antibody levels compatible with protection. The formulation elicits balanced IgG subclasses and T‐helper 1 cell‐type cellular responses, supporting effective immune mechanisms. These findings suggest that NLC‐based delivery of M2e peptides, especially with helper epitopes, represents a promising universal influenza vaccine strategy warranting further preclinical and clinical investigation.