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

Messenger RNA (mRNA), which is composed of ribonucleotides that carry genetic information and direct protein synthesis, is transcribed from a strand of DNA as a template. On this basis, mRNA technology can take advantage of the body’s own translation system to express proteins with multiple functions for the treatment of various diseases. Due to the advancement of mRNA synthesis and purification, modification and sequence optimization technologies, and the emerging lipid nanomaterials and other delivery systems, mRNA therapeutic regimens are becoming clinically feasible and exhibit significant reliability in mRNA stability, translation efficiency, and controlled immunogenicity. Lipid nanoparticles (LNPs), currently the leading non-viral delivery vehicles, have made many exciting advances in clinical translation as part of the COVID-19 vaccines and therefore have the potential to accelerate the clinical translation of gene drugs. Additionally, due to their small size, biocompatibility, and biodegradability, LNPs can effectively deliver nucleic acids into cells, which is particularly important for the current mRNA regimens. Therefore, the cutting-edge LNP@mRNA regimens hold great promise for cancer vaccines, infectious disease prevention, protein replacement therapy, gene editing, and rare disease treatment. To shed more lights on LNP@mRNA, this paper mainly discusses the rational of choosing LNPs as the non-viral vectors to deliver mRNA, the general rules for mRNA optimization and LNP preparation, and the various parameters affecting the delivery efficiency of LNP@mRNA, and finally summarizes the current research status as well as the current challenges. The latest research progress of LNPs in the treatment of other diseases such as oncological, cardiovascular, and infectious diseases is also given. Finally, the future applications and perspectives for LNP@mRNA are generally introduced.

/pdf/recent-advances-in-lipid-nanoparticles-for-delivery-of-mrna-1u86o4l6.pdf

Recent Advances in Lipid Nanoparticles for Delivery of mRNA

Compared to other vaccines, the inherent properties of messenger RNA (mRNA) vaccines and their interaction with lipid nanoparticles make them considerably unstable throughout their life cycles, impacting their effectiveness and global accessibility. It is imperative to improve mRNA vaccine stability and investigate the factors influencing stability. Since mRNA structure, excipients, lipid nanoparticle (LNP) delivery systems, and manufacturing processes are the primary factors affecting mRNA vaccine stability, optimizing mRNA structure and screening excipients can effectively improve mRNA vaccine stability. Moreover, improving manufacturing processes could also prepare thermally stable mRNA vaccines with safety and efficacy. Here, we review the regulatory guidance associated with mRNA vaccine stability, summarize key factors affecting mRNA vaccine stability, and propose a possible research path to improve mRNA vaccine stability.

Research Advances on the Stability of mRNA Vaccines

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two‐pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in “two‐in‐one” nanocarriers (NAHA‐CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro‐chondrogenic TGF‐β1 mRNA (≈1.3‐fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti‐inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid‐induced early and late OA mouse models and a surgical destabilization of medial meniscus‐induced OA rat model. Therefore, the siCA9 and NO scavenger “two‐in‐one” delivery system is a potential and efficient strategy for progressive OA treatment.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/advs.202207490

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, different strategies to efficiently deliver nucleic acid delivery from LNPs are concluded and their mechanisms are investigated. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, the issues that are necessary to be approached in the clinical translation of LNPs are discussed, which it is hoped will shed light on the development of LNP nucleic acid drugs.

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid.

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, most current mRNA delivery platforms need to be stored at -20 °C or -70 °C due to their poor stability, which severely restricts their availability. Herein, we develop a lyophilization technique to prepare SARS-CoV-2 mRNA-lipid nanoparticle vaccines with long-term thermostability. The physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques. Furthermore, in the human trial, administration of lyophilized Omicron mRNA vaccine as a booster shot also engendered strong immunity without severe adverse events, where the titers of neutralizing antibodies against Omicron BA.1/BA.2/BA.4 were increased by at least 253-fold after a booster shot following two doses of the commercial inactivated vaccine, CoronaVac. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity and significantly improves their accessibility, particularly in remote regions. 

https://www.nature.com/articles/s41421-022-00517-9.pdf

Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2

Given the tremendous increase in the risks of cartilage defects in the sports and aging population, current treatments are limited, and new repair strategies are needed. Cartilage tissue engineering (CTE) is a promising approach to handle this burden and several fabrication technologies and biomaterials have been developed these years. The extracellular matrix (ECM) of cartilage consists of a tissue-specific 3D microenvironment with excellent biomechanical and biochemical properties, which regulates cell proliferation, adhesion, migration, and differentiation, thus attracting a great deal of attention to the rapid development of CTE based on ECM components. New generations of biomaterials are being developed rapidly for use as scaffolds to mimic the natural ECM environment. In this review, we discuss such CTE scaffolds based on ECM-derived biomaterials by reviewing the biomaterials for CTE, the applications in different scaffolds and their processing approaches, as well as the current clinical applications of those ECM-based CTE scaffolds. 

The application of ECM-derived biomaterials in cartilage tissue engineering

The meniscus is a fibrocartilaginous tissue of the knee joint that plays an important role in load transmission, shock absorption, joint stability maintenance, and contact stress reduction. Mild meniscal injuries can be treated with simple sutures, whereas severe injuries inevitably require meniscectomy. Meniscectomy destroys the mechanical microenvironment of the knee joint, leading to cartilage degeneration and osteoarthritis. Tissue engineering techniques, as a strategy with diverse sources and customizable and adjustable mechanical and biological properties, have emerged as promising approaches for the treatment of meniscal injuries and are represented by 3D printing. Notably, the heterogeneity of the meniscus, including its anatomical structure, cell phenotype, extracellular matrix, and biomechanical properties, is crucial for its normal function. Therefore, the construction of heterogeneous tissue-engineered menisci (TEM) has become a research hotspot in this field. In this review, we systematically summarize the heterogeneity of menisci and 3D-printed strategies for tissue-engineered anisotropic menisci. The manufacturing techniques, biomaterial combinations, surface functionalization, growth factors, and bioreactors related to 3D-printed strategies are introduced and a promising direction for the future research is proposed.

Meniscus heterogeneity and 3D-printed strategies for engineering anisotropic meniscus

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Papers

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2

The application of ECM-derived biomaterials in cartilage tissue engineering

Meniscus heterogeneity and 3D-printed strategies for engineering anisotropic meniscus