A Poly(lactic Acid)‐Porphyrin‐Cobalt Vaccine Adjuvant System Elicits Protein‐ or Peptide‐Specific Humoral and Cellular Immunity

ABSTRACT There is growing interest in vaccine adjuvant systems that are scalable, adaptable, and capable of stimulating humoral and cellular immune responses with recombinant protein or synthetic peptide immunogens. In this study, we introduced a “plug‐and‐play” nanoadjuvant system consisting of poly(lactic acid)‐porphyrin‐cobalt ion co‐formulated with immunostimulatory saponin QS‐21 (PPCoQ). PPCoQ facilitated subunit vaccine assembly by coordinating antigens' polyhistidine tags with immobilized cobalt (Co 2+ ) within a porphyrin‐modified poly(lactic acid). Using the receptor‐binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) as a model antigen, the resulting nanovaccine, PPCoQ‐RBD, induced high levels of anti‐RBD antibodies in transgenic mice expressing human ACE2. Following viral challenge, immunized mice achieved a 99.7% clearance rate of the SARS‐CoV‐2 Omicron variant, demonstrating strong humoral and cellular immune responses. Additionally, PPCoQ‐RBD was compatible with nebulization‐based inhalation, which enhanced mucosal immunity, increased IgA antibody titers, and promoted the formation of abundant tissue‐resident memory T cells. A model T cell epitope (OVA) was formulated to evaluate cellular responses, generating PPCoQ‐OVA, which significantly inhibited B16‐OVA tumor growth. The PPCoQ vaccine adjuvant system is easy to produce and supports efficient antigen loading, lymph node targeting, lysosomal escape, and biocompatibility, and has broad prospects for application and clinical translation.