Ahead of his 45th birthday, Feng Zhang, James and Patricia Poitras Professor of Neuroscience at the Massachusetts Institute of Technology, discussed his life in science.
Ionizable lipid nanoparticles have emerged as a potent non-viral delivery platform for nucleic acid therapeutics, achieving clinical breakthroughs ranging from the FDA-approved small interfering RNA therapeutic to mRNA vaccines against coronavirus disease 2019 and respiratory syncytial virus. Their success stems from the ability of ionizable lipids to remain neutral in physiological environments, yet protonate in acidic endosomes, enabling the efficient release of genetic cargo. Over the last several decades, their structures have evolved extensively through the application of combinatorial chemistry, rational design, incorporation of functional elements and, most recently, machine learning and artificial intelligence-guided strategies. These innovations have expanded ionizable lipids from passive carriers into multifunctional materials capable of organ-specific targeting, responsiveness, immunomodulation and theranostics. In this Review, we highlight the development, synthesis and structural evolution of ionizable lipids as well as their emerging on-demand design functionalities and next-generation biomedical applications. We provide insights into the challenges and gaps for translation, manufacturing and expansion of lipid nanoparticle-mediated nucleic acid therapeutics for precision RNA medicine. Ionizable lipids represent central components in nucleic acid therapeutics. This Review outlines their structural evolution, design strategies and emerging functions while highlighting next-generation principles and translational perspectives that may guide precision RNA therapeutics in regenerative medicines.
Understanding organic chemistry in water presents challenges distinct from those encountered in conventional organic solvents. Reaction media are usually heterogeneous and contain colloidal objects (micelles and emulsion droplets) and undissolved solids; however, the analytical tools commonly used to study organic reaction mechanisms are often not well suited to such systems or require substantial adaptation deviating from synthetic conditions. As a result, the development and optimization of reactions proceed as though emulsion droplets are a 'magic box', in which progress is identified through inefficient trial-and-error approaches. Here we highlight outstanding mechanistic questions in aqueous-organic chemistry. Through case studies in selectivity control, trial-and-error reaction optimization and surfactant-free systems, we identify key gaps in mechanistic understanding. Finally, using analytical case studies in small-angle X-ray scattering, NMR spectroscopy, dynamic light scattering, cryo-transmission electron microscopy and fluorescence microscopy, we analyse the scope and limitations of current analytical methods in these systems and discuss opportunities for advancing mechanistic insight.
This article highlights a newly developed chemically fuelled logic gate whereby a single porphyrin dye is driven by two independent enzyme reactions, one setting its colour and the other its fluorescence. Because the two outputs recover on separately tunable timescales, the system produces a programmable delay of up to about 23 minutes between them, letting the researchers control not just whether a signal appears but when.
Bruno Pinheiro explains the workings of their custom-made apparatus for measuring vapour pressures with high accuracy within large pressure and temperature ranges.
