"Abstract
Efficient and accurate nanocarrier development for targeted drug delivery is hindered by a lack of methods to analyze its cell-level biodistribution across whole organisms. Here we present Single Cell Precision Nanocarrier Identification (SCP-Nano), an integrated experimental and deep learning pipeline to comprehensively quantify the targeting of nanocarriers throughout the whole mouse body at single-cell resolution. SCP-Nano reveals the tissue distribution patterns of lipid nanoparticles (LNPs) after different injection routes... We demonstrate that intramuscularly injected LNPs carrying SARS-CoV-2 spike mRNA reach heart tissue, leading to proteome changes, suggesting immune activation and blood vessel damage...
Main
Modern biomedical science offers a vast array of macromolecular drugs (for example, various RNA species, genome editing tools and protein drugs) with the potential to reverse disease-causing alterations in the human body. However, a major hurdle in their clinical translation lies in delivering these large, charged molecules specifically to target cell populations while minimizing off-target effects...
Nanocarriers, such as lipid nanoparticles (LNPs), liposomes, apolyplexes and viral vectors, such as adeno-associated viruses (AAVs), are among the most promising delivery solutions. They protect drug molecules, help to overcome biological barriers and can mediate organ and cell type targeting... [U]pon exposure to the in vivo environment, nanocarriers can influence their biodistribution and cellular interactions, complicating nanocarrier design and the prediction of target tissue.
A critical challenge across all nanocarrier strategies is maximizing specificity and efficiency for target tissues and cells while minimizing adverse and off-target effects...
SCP-Nano [Single Cell Precision Nanocarrier Identification] should accelerate the development of precise and safe nanocarrier-based therapeutics...
Results
SCP-Nano reveals tropism of LNP's via different routes: ... Notably, the resolution of SCP-Nano revealed localized hotspots within organs, such as in the liver and spleen... that would be difficult to discern with conventional methods...
SCP-Nano reveals potential off-targeting effects: ... Given that MC3 [ionizable lipid]-based LNPs are used in RNA therapeutics and drug development ... we further explored potential effects of the LNP-driven mRNA expressions in the heart...
[W]e found the spike protein primarily within the endothelial cells of heart capillaries...
The observed LNP accumulation and proteome changes in heart tissue suggest a potential mechanism by which LNP-based mRNA vaccines could contribute to the reported cardiac complications... Thus, the potential causative mechanisms that we identified need to be explored further in future work."
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