Conspectus
Since the U.S. Food and Drug Administration
(FDA) granted emergency
use authorization for two mRNA vaccines against SARS-CoV-2, mRNA-based
technology has attracted broad attention from the scientific community
to investors. When delivered intracellularly, mRNA has the ability
to produce various therapeutic proteins, enabling the treatment of
a variety of illnesses, including but not limited to infectious diseases,
cancers, and genetic diseases. Accordingly, mRNA holds significant
therapeutic potential and provides a promising means to target historically
hard-to-treat diseases. Current clinical efforts harnessing mRNA-based
technology are focused on vaccination, cancer immunotherapy, protein
replacement therapy, and genome editing. The clinical translation
of mRNA-based technology has been made possible by leveraging nanoparticle
delivery methods. However, the application of mRNA for therapeutic
purposes is still challenged by the need for specific, efficient,
and safe delivery systems.
This Account highlights key advances
in designing and developing
combinatorial synthetic lipid nanoparticles (LNPs) with distinct chemical
structures and properties for in vitro and in vivo intracellular mRNA delivery. LNPs represent the
most advanced nonviral nanoparticle delivery systems that have been
extensively investigated for nucleic acid delivery. The aforementioned
COVID-19 mRNA vaccines and one LNP-based small interfering RNA (siRNA)
drug (ONPATTRO) have received clinical approval from the FDA, highlighting
the success of synthetic ionizable lipids for in vivo nucleic acid delivery. In this Account, we first summarize the research
efforts from our group on the development of bioreducible and biodegradable
LNPs by leveraging the combinatorial chemistry strategy, such as the
Michael addition reaction, which allows us to easily generate a large
set of lipidoids with diverse chemical structures. Next, we discuss
the utilization of a library screening strategy to identify optimal
LNPs for targeted mRNA delivery and showcase the applications of the
optimized LNPs in cell engineering and genome editing. Finally, we
outline key challenges to the clinical translation of mRNA-based therapies
and propose an outlook for future directions of the chemical design
and optimization of LNPs to improve the safety and specificity of
mRNA drugs. We hope this Account provides insight into the rational
design of LNPs for facilitating the development of mRNA therapeutics,
a transformative technology that promises to revolutionize future
medicine.