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mRNA vaccines have evolved from being a mere curiosity to emerging as COVID-19 vaccine front-runners. Recent advancements in the field of RNA technology, vaccinology, and nanotechnology have generated interest in delivering safe and effective mRNA therapeutics. In this review, we discuss design and self-assembly of mRNA vaccines. Self-assembly, a spontaneous organization of individual molecules, allows for design of nanoparticles with customizable properties. We highlight the materials commonly utilized to deliver mRNA, their physicochemical characteristics, and other relevant considerations, such as mRNA optimization, routes of administration, cellular fate, and immune activation, that are important for successful mRNA vaccination. We also examine the COVID-19 mRNA vaccines currently in clinical trials. mRNA vaccines are ready for the clinic, showing tremendous promise in the COVID-19 vaccine race, and have pushed the boundaries of gene therapy., Graphical abstract Unlabelled Image, Highlights • mRNA vaccines showed spectacular success in the race for COVID-19 vaccines. • Design of both mRNA and the delivery vectors help in fine-tuning efficacy. • Self-assembled mRNA delivery vectors include lipid and polymer nanoparticles. • Lipid nanoparticle mRNA vaccines have ca. 95% efficacy and earned EUA FDA approval. • These unprecedented results may pave the road for future mRNA vaccine development.

The complexity of nanoscale interactions between biomaterials and cells has limited the realization of the ultimate vision of nanotechnology in diagnostics and therapeutics. As such, significant effort has been devoted to advancing our understanding of the biophysical interactions of the myriad nanoparticles. Endocytosis of nanomedicine has drawn tremendous interest in the last decade. Here, we highlight the ever-present barriers to efficient intracellular delivery of nanoparticles as well as the current advances and strategies deployed to breach these barriers. We also introduce new barriers that have been largely overlooked such as the glycocalyx and macromolecular crowding. Additionally, we draw attention to the potential complications arising from the disruption of the newly discovered functions of the lysosomes. Novel strategies of exploiting the inherent intracellular defects in disease states to enhance delivery and the use of exosomes for bioanalytics and drug delivery are explored. Furthermore, we discuss the advances in imaging techniques like electron microscopy, super resolution fluorescence microscopy, and single particle tracking which have been instrumental in our growing understanding of intracellular pathways and nanoparticle trafficking. Finally, we advocate for the push towards more intravital analysis of nanoparticle transport phenomena using the multitude of techniques available to us. Unraveling the underlying mechanisms governing the cellular barriers to delivery and biological interactions of nanoparticles will guide the innovations capable of breaching these barriers.