Enantiomer-dependent and modification-free DNA matrix as an adjuvant for subunit vaccines against SARS-CoV-2 or pneumococcal infections.

The emergence of novel infectious disease has intensified demand for more advanced vaccine development and more potent adjuvants to enhance immunogenicity. Here we introduce a dynamic DNA supramolecular matrix assembled from five unmodified, short DNA single strands, serving as a safe, multifaceted adjuvant platform. This DNA matrix elicits a robust humoral response with minimal adverse effects, generating potent neutralizing antibodies and conferring robust protection against SARS-CoV-2 and Streptococcus pneumoniae infections. Its dynamic colloidal feature prolongs the in vivo retention of both DNA and antigen, facilitating lymphatic-targeted transportation and presentation. This process leads to a robust pro-inflammatory response in both the vaccinated site and draining lymph node, which, in turn, promotes the recruitment and activation of immune cells, leading to a rapid, effective antigen-specific antibody response. The enhanced function of DNA matrix depends on the canonical TLR9-MyD88 signalling axis in dendritic cells. In addition, only right-handed, not left-handed, chirality of the DNA strands forms D-DNA matrix and promotes immune activations. Thus, this DNA matrix functions as an all-in-one adjuvant platform, opening promising avenues for future vaccine design.