Messenger RNA (mRNA) vaccines have emerged as a transformative technology in cancer immunotherapy and infectious disease prevention. mRNA vaccines deliver synthetic mRNA encoding target antigens into host cells, where the mRNA is translated into proteins that elicit adaptive immune responses. However, their clinical potential 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 (JACS), a research team led by YU Haijun from the Shanghai Institute of Materia Medica (SIMM) of Chinese Academy of Sciences, in collaboration with XU Zhiai from East China Normal University, developed an ultrasound-activatable lipid nanoparticle (ULNP) platform that enabled region-confined innate immune stimulation and enhanced mRNA vaccine efficacy against cancer. The paper was selected as the Front Cover by the editorial team of JACS. 

The researchers innovatively designed a sonosensitive adjuvant lipid, namely sono-adjuvant lipid, by integrating the clinically approved sonosensitizer hematoporphyrin monomethyl ether (HMME) into the lipid structure. Upon exposure to ultrasound stimulation, the sono-adjuvant lipid generated reactive oxygen species (ROS), which transiently increased lysosomal membrane permeability, promoted cytosolic mRNA release, and activated multiple innate immune pathways in antigen-presenting cells (APCs), such as the stimulator of interferon genes (STING) and Toll-like receptor-9 (TLR9) pathways.

The combination of mRNA-loaded ULNP with localized ultrasound stimulation (ULNP+US) markedly enhanced DCs maturation 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 model, the combination of circular RNA (circRNA)-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 in mice.

The spatiotemporal-tunable vaccination strategy displayed markedly improved biosafety and transfection efficacy compared with the traditional mRNA vaccines. Through converting the physical ultrasound stimuli into a biological immune trigger, ULNP platform achieved region-confined innate immune stimulation and mRNA-encoded tumor antigen presentation, offering 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 marked an important step toward noninvasive and programmable cancer vaccine immunotherapy.

DOI: 10.1021/jacs.5c06028

Link: https://pubs.acs.org/doi/10.1021/jacs.5c06028

Keywords: Ultrasound-activatable, Lipid nanoparticle, mRNA vaccine

An ultrasound-activatable lipid nanoparticle platform was engineered to endow the conventional mRNA vaccines with stimuli-controllable adjuvanticity. (Image by CHEN Fangmin).

Contact:

DIAO Wentong

Shanghai Institute of Materia Medica

E-mail: diaowentong@simm.ac.cn