Researchers from the Innovation Academy for Precision Measurement Science and Technology (APM) of the Chinese Academy of Sciences have developed a novel lipid nanoparticle system with an intrinsic imaging capability that enables both efficient mRNA delivery and real-time, non-invasive in vivo tracking. This system provides a powerful tool for understanding the relationships between mRNA delivery, protein expression, and immune activation.

The study was published in PNAS on January 2.

mRNA molecules are unstable and quickly degrade in vivo, making LNPs essential for their delivery. However, traditional LNPs have two limitations. First, their in vivo fate is difficult to determine. Second, a substantial fraction of the administered dose undergoes non-specific hepatic uptake. This off-target accumulation reduces delivery efficiency to the intended tissue and raises potential safety concerns, thereby constraining mechanistic studies and translational applications.

To address these issues, researchers led by ZHOU Xin introduced fluorinated structural motifs into LNPs, creating a new class of fluorinated lipid nanoparticles (FLNPs). The incorporated fluorine serves as a highly specific 19F magnetic resonance imaging (MRI) tracer. Since endogenous 19F background signals in the body are negligible, this strategy allows for clear, quantitative visualization of nanocarrier biodistribution in vivo.

Experimental results demonstrate that FLNPs maintain mRNA expression efficiency comparable to that of clinically used LNPs, while reducing non-specific liver accumulation by up to 94.6%. Importantly, this system enables continuous in vivo monitoring of nanocarrier distribution, mRNA release, and the spatiotemporal dynamics of antigen expression—capabilities that were previously difficult to achieve.

Building on this imaging platform, the researchers integrated FLNP tracking with immunological analyses to establish a coherent in vivo sequence linking nanocarrier localization, antigen expression, and immune cell behavior. The results show that immune activation is initiated locally at the injection site, followed by the migration of antigen-presenting cells to draining lymph nodes, thereby completing the early and essential steps of immune response initiation.

Addressing the central question of how mRNA vaccines function in vivo from both dynamic and mechanistic perspectives, this study provides direct experimental evidence of the spatiotemporal processes underlying immune activation.

The FLNP platform, which combines precise delivery with non-invasive real-time tracking and offers a robust technological foundation for the rational design, safety assessment, and efficacy monitoring of next-generation mRNA vaccines and nucleic acid therapeutics.

This work was supported by the Ministry of Science and Technology of China, the National Natural Science Foundation of China, and the Chinese Academy of Sciences, among others.