Engineering intramolecular adjuvants for next-generation vaccines

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.