The dawn of mRNA vaccines: The COVID-19 case.

https://doi.org/10.1016/j.xphs.2022.11.001

The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

Lipid nanoparticles (LNPs) are the most clinically advanced delivery system for RNA-based drugs but have predominantly been investigated for intravenous and intramuscular administration. Subcutaneous administration opens the possibility of patient self-administration and hence long-term chronic treatment that could enable messenger RNA (mRNA) to be used as a novel modality for protein replacement or regenerative therapies. In this study, we show that subcutaneous administration of mRNA formulated within LNPs can result in measurable plasma exposure of a secreted protein. However, subcutaneous administration of mRNA formulated within LNPs was observed to be associated with dose-limiting inflammatory responses. To overcome this limitation, we investigated the concept of incorporating aliphatic ester prodrugs of anti-inflammatory steroids within LNPs, i.e., functionalized LNPs to suppress the inflammatory response. We show that the effectiveness of this approach depends on the alkyl chain length of the ester prodrug, which determines its retention at the site of administration. An unexpected additional benefit to this approach is the prolongation observed in the duration of protein expression. Our results demonstrate that subcutaneous administration of mRNA formulated in functionalized LNPs is a viable approach to achieving systemic levels of therapeutic proteins, which has the added benefits of being amenable to self-administration when chronic treatment is required.

Functionalized lipid nanoparticles for subcutaneous administration of mRNA to achieve systemic exposures of a therapeutic protein

Lipid‐based nanoparticles have emerged as a clinically viable platform technology to deliver nucleic acids for a wide range of healthcare applications. Within this scope, one of the most exciting areas of recent progress and future innovation potential lies in the material science of lipid‐based nanoparticles, both to refine existing nanoparticle strategies and to develop new ones. Herein, the latest efforts to develop next‐generation lipid‐based nanoparticles are covered by taking a nanoarchitectonics perspective and the design, nucleic acid encapsulation methods, scalable production, and application prospects are critically analyzed for three classes of lipid‐based nanoparticles: 1) traditional lipid nanoparticles (LNPs); 2) lipoplexes; and 3) bicelles. Particular focus is placed on rationalizing how molecular self‐assembly principles enable advanced functionalities along with comparing and contrasting the different nanoarchitectures. The current development status of each class of lipid‐based nanoparticle is also evaluated and possible future directions in terms of overcoming clinical translation challenges and realizing new application opportunities are suggested.

Lipid Nanoparticle Technologies for Nucleic Acid Delivery: A Nanoarchitectonics Perspective

The review considers liposomes as systems of substantial interest as adjuvant carriers in vaccinology due to their versatility and maximal biocompatibility. Research and development on the use of liposomes and lipid nanoparticles to create subunit vaccines for the prevention and treatment of infectious diseases has been going on for several decades. In recent years, the area has seen serious progress due to the improvement of the technology of industrial production of various high-grade lipids suitable for parenteral administration and the emergence of new technologies and equipment for the production of liposomal preparations. When developing vaccines, it is necessary to take into account how the body's immune system (innate and adaptive immunity) functions. The review briefly describes some of the fundamental mechanisms underlying the mobilization of immunity when encountering an antigen, as well as the influence of liposome carriers on the processes of internalization of antigens by immunocompetent cells and ways of immune response induction. The results of the studies on the interactions of liposomes with antigen-presenting cells in function of the liposome size, charge, and phase state of the bilayer, which depends on the lipid composition, are often contradictory and should be verified in each specific case. The introduction of immunostimulant components into the composition of liposomal vaccine complexes-ligands of the pathogen-associated molecular pattern receptors-permits modulation of the strength and type of the immune response. The review briefly discusses liposome-based vaccines approved for use in the clinic for the treatment and prevention of infectious diseases, including mRNA-loaded lipid nanoparticles. Examples of liposomal vaccines that undergo various stages of clinical trials are presented. 

/pdf/liposomes-as-adjuvants-and-vaccine-delivery-systems-171eubfs.pdf

Liposomes as Adjuvants and Vaccine Delivery Systems

https://doi.org/10.1016/j.ccell.2023.05.004

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.

Effect of complexing lipids on cellular uptake and expression of messenger RNA in human skin explants.

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Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.

Effect of complexing lipids on cellular uptake and expression of messenger RNA in human skin explants.