Nasal vaccines offer advantages in eliciting mucosal immunity, particularly through the induction of dimeric IgA. However, the complex mucosal environment poses challenges in achieving optimal immunogenicity and safety. This study introduced Diprovocim, a TLR2 agonist, as an effective and safe adjuvant for mucosal vaccines. Our results demonstrated that Diprovocim self-assembled into particles of suitable size for mucosal delivery, enhancing antigen phagocytosis of immune cells in both lymph nodes and lungs. After effectively activating the TLR2 signaling pathway, Diprovocim led to a reduced release of inflammatory cytokines in vivo without any tissue damage or weight loss, highlighting its safety profile. In mice, both intramuscular and intranasal immunization with Diprovocim-adjuvanted vaccines induced high titers of systemic antibodies. Higher IgG and IgA antibodies were detected in bronchoalveolar lavage fluid (BALF). Moreover, Diprovocim enhanced the immunogenicity of ovalbumin (OVA) and recombinant SARS-CoV-2 protein (RFD-Fc) vaccines, achieving higher CD4(+) and CD8(+) T cell immune responses and cross-protection against SARS-CoV-2 variants. These findings highlight the potential of self-assembled Diprovocim as a safe and effective adjuvant for mucosal vaccines, offering a promising strategy for combating respiratory infections.