Delivery Systems of mRNA Vaccines in the Treatment of Infectious Diseases: From Lipid Nanoparticles to Next-Generation Platforms

The historic accomplishment of mRNA vaccines against SARS-CoV-2 has provided a massive shift in vaccinology, providing a quick, nimble, and powerful platform for infectious disease prevention. This success, however, does not simply stem from the mRNA sequence but equally depends on the delivery vehicle-the lipid nanoparticle (LNP). The delivery system has evolved from a passive transporter into an active immunomodulatory component, a critical component that (1) protects the inherently fragile mRNA payload, (2) allows cellular uptake and endosomal escape, and (3) adds its own inherent adjuvant properties to shape the immune response. This review provides a comprehensive summary of the current advancements in mRNA vaccine delivery technologies. We first deconstruct the structure, mechanisms, advantages, and disadvantages of the clinically validated LNP platform. Following this discussion, we highlight the emerging landscape of new systems, including chemically diverse polymeric nanoparticles, biologically-inspired peptide-based carriers, and endogenous extracellular vesicles, potentially overcome current limitations in these delivery systems, including issues with thermostability and targeted delivery. After this, we summarize how these new delivery technologies are being leveraged clinically for a continuum of high-priority infectious diseases, including influenza, RSV, CMV, HIV, Zika, and Rabies. This discussion also illustrates how the design of vaccine prototypes is being rational to address the immune-mediated strategies exploited by each distinct pathogen.