Engineering intramolecular adjuvants for next-generation vaccines
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GRAPHICAL ABSTRACT
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PUBLIC SUMMARY
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Intramolecular adjuvants fuse adjuvants with antigens into one molecule for precise immune activation.
Four major classifications: bacterial toxin derivatives, PRR ligands, cytokines and complement fragments.
This toolkit enables programmable immunity for next-generation vaccine design.
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ABSTRACT
Vaccines play a pivotal role in reducing the global burden of infectious diseases. Currently, vaccine development is transitioning from empirical approaches toward precision engineering. The intramolecular adjuvant strategy, which fuses adjuvants and antigens into single molecules via genetic engineering, emerges as a promising strategy with the potential to play a key role in this transition. Through precise control of co-delivery and synergistic signaling, intramolecular adjuvants can modulate the magnitude, duration, and type of immune response, thereby advancing vaccine design toward a more programmable paradigm, in which immune activation can be rationally tuned at the molecular level, ultimately enabling “programmable immunity”. This review systematically summarizes the current toolbox of genetically encoded intramolecular adjuvants, including derivatives of bacterial toxins, pattern recognition receptor (PRR) ligands, cytokines, and the complement fragments. By integrating structural biology, synthetic biology, and immunology, we delineate their mechanisms in receptor-targeted delivery and synergistic immune pathway activation. Notably, artificial intelligence (AI) might accelerate the rational development of intramolecular adjuvants via sequence mining, structural optimization and de novo design. Collectively, this review aims to establish a systematic framework for intramolecular adjuvant selection and design, advancing a data-driven paradigm to counter emerging pathogens. -
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Wang Y., Liao W., Zhang Z., et al. (2026). Engineering intramolecular adjuvants for next-generation vaccines. The Innovation Medicine 4:100258. https://doi.org/10.59717/j.xinn-med.2026.100258
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Wang Y., Liao W., Zhang Z., et al. (2026). Engineering intramolecular adjuvants for next-generation vaccines. The Innovation Medicine 4:100258. https://doi.org/10.59717/j.xinn-med.2026.100258
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Figure 1.
Schematic overview of intramolecular adjuvant–antigen fusion constructs and their delivery pathways
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Figure 2.
Mechanistic classification and signaling pathways of four major genetically engineered intramolecular adjuvants
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Figure 3.
AI-driven intelligent design platform for intramolecular adjuvants.
