Messenger RNA (mRNA) vaccines have emerged as a transformative technology in cancer immunotherapy and infectious disease prevention. They deliver synthetic mRNA encoding target antigens into host cells where the mRNA is translated into proteins that elicit adaptive immune responses. 

However, the clinical potential of mRNA vaccines is limited by insufficient innate immune activation and safety issues caused by conventional adjuvants that continuously stimulate the immune system. Achieving precise spatial and temporal control of immune activation remains a major challenge in the design of effective and safe mRNA vaccines.

In a study published in Journal of the American Chemical Society as the front cover story, a research team led by YU Haijun from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences, along with XU Zhiai from East China Normal University, developed an ultrasound-activatable lipid nanoparticle (ULNP) platform that enables region-confined innate immune stimulation and enhances mRNA vaccine efficacy against cancer.

By integrating the clinically approved sonosensitizer hematoporphyrin monomethyl ether into the lipid structure, researchers designed a sonosensitive adjuvant lipid, sono-adjuvant lipid. Upon exposure to ultrasound stimulation, the sono-adjuvant lipid generated reactive oxygen species, which transiently increased lysosomal membrane permeability, promoted cytosolic mRNA release, and activated multiple innate immune pathways in antigen-presenting cells such as the stimulator of interferon genes and Toll-like receptor-9 pathways.

Combining mRNA-loaded ULNP with localized ultrasound stimulation markedly enhanced the maturation of dendritic cells and antigen cross-presentation in lymph nodes, leading to a 2.5-fold higher antigen-specific CD8⁺ T cell response compared with conventional adjuvant-based mRNA vaccines. 

In an orthotopic liver cancer mice model, combining circular RNA-loaded ULNP with ultrasound stimulation effectively promoted tumor neoantigen presentation and activated neoantigen-specific T cell immunity, resulting in complete tumor eradication and 100% long-term survival.

The spatiotemporal-tunable vaccination strategy shows markedly improved transfection efficacy and biosafety compared with traditional mRNA vaccines. By converting the physical ultrasound stimuli into a biological immune trigger, the ULNP platform offers a controllable strategy to enhance tumor-specific immune responses while reducing off-target inflammatory effects. The integration of ultrasound-activatable sonodynamic chemistry with mRNA nanomedicine marks an important step toward noninvasive and programmable cancer vaccine immunotherapy.