A pathogen-mimicking nanovaccine orchestrating danger recognition and immune activation for potent cellular immunity.

Vaccines protect against infectious diseases by mimicking pathogens and delivering key signals required for immune activation. However, how to rationally emulate pathogen invasion processes to achieve potent cellular immunity remains a major challenge in vaccine design. Here, we propose a pathogen-mimicking delivery strategy based on the sequential processes of "danger recognition" and "immune activation". Mannatide derived from Streptococcus α-hemolyticus was incorporated into the formulation to mimic pathogen-associated carbohydrate structures, thereby promoting mannose receptor-mediated antigen-presenting cell (APC) targeting and immune recognition. Acting as a pathogen-associated "danger signal", mannatide facilitates APC recognition and provides the foundation for downstream immune activation. To further amplify immune responses, we identified escin sodium (Esc), screened from clinically used saponin molecules, as a novel immunostimulatory agent capable of activating APCs through interferon-associated signaling pathways. Using highly adsorptive aluminum hydroxide as the "pathogen structural scaffold", we developed a one-step microfluidic-assisted assembly strategy to construct aluminum hydroxide-mannatide nanovaccines (AlMN) co-loaded with antigen and Esc. AlMN markedly enhanced APC maturation, antigen-specific CD8+ T-cell activation, and durable immunological memory in vivo. In a TC-1 tumor model expressing human papillomavirus (HPV)-associated antigens, AlMN vaccination significantly delayed tumor progression, while combination with anti-PD-1 therapy further improved survival. Collectively, this pathogen-mimicking strategy integrating "danger recognition" and "immune activation" provides a conceptual framework for the rational design and optimization of next-generation vaccine delivery systems.