Alkyl chain engineering of ionic AIE molecules for developing superior self-adjuvanted nanovaccines in cancer immunotherapy

Cancer nanovaccines represent a promising approach to cancer immunotherapy, offering advantages such as safety, efficacy, and personalization. However, challenges such as complex compositions, limited structural control, and significant side effects impede their clinical application. In this study, we developed a strategy for preparing nanovaccines through the co-assembly of well-defined single-component organic small molecules with antigens. By carefully adjusting the length of alkyl chains within the small molecules, we achieved precise control over the assembly behavior of the final nanovaccines and optimized their antigen-loading efficiency. After elucidating the relationship between molecular structure and the resulting nanovaccine assemblies, we identified the small molecule TCSVP, which serves as both a potent adjuvant and an effective antigen carrier. Interestingly, TCSVP efficiently activates the STING pathway in dendritic cells. Furthermore, in three preventive tumor models, TCSVP achieved a complete resistance rate of ≥ 50 % against tumor inoculation and established robust immune memory lasting up to 135 days. Additionally, compared to commercially available complete Freund's adjuvant, TCSVP demonstrated superior immune activation while exhibiting negligible immune-related inflammatory side effects, indicating a favorable safety and efficacy profile. This work not only highlights the significant potential of single-component small molecules in the development of advanced nanovaccines but also provides valuable insights for the design of small molecule-based self-adjuvanting nanovaccines.