Ionizable lipid nanoparticles for in utero mRNA delivery.

Clinical advances enable the prenatal diagnosis of genetic diseases that are candidates for gene and enzyme therapies such as messenger RNA (mRNA)-mediated protein replacement. Prenatal mRNA therapies can treat disease before the onset of irreversible pathology with high therapeutic efficacy and safety due to the small fetal size, immature immune system, and abundance of progenitor cells. However, the development of nonviral platforms for prenatal delivery is nascent. We developed a library of ionizable lipid nanoparticles (LNPs) for in utero mRNA delivery to mouse fetuses. We screened LNPs for luciferase mRNA delivery and identified formulations that accumulate within fetal livers, lungs, and intestines with higher efficiency and safety compared to benchmark delivery systems, DLin-MC3-DMA and jetPEI. We demonstrate that LNPs can deliver mRNAs to induce hepatic production of therapeutic secreted proteins. These LNPs may provide a platform for in utero mRNA delivery for protein replacement and gene editing

Vaccine Technologies and Platforms for Infectious Diseases: Current Progress, Challenges, and Opportunities

Vaccination is a key component of public health policy with demonstrated cost-effective benefits in protecting both human and animal populations. Vaccines can be manufactured under multiple forms including, inactivated (killed), toxoid, live attenuated, Virus-like Particles, synthetic peptide, polysaccharide, polysaccharide conjugate (glycoconjugate), viral vectored (vector-based), nucleic acids (DNA and mRNA) and bacterial vector/synthetic antigen presenting cells. Several processes are used in the manufacturing of vaccines and recent developments in medical/biomedical engineering, biology, immunology, and vaccinology have led to the emergence of innovative nucleic acid vaccines, a novel category added to conventional and subunit vaccines. In this review, we have summarized recent advances in vaccine technologies and platforms focusing on their mechanisms of action, advantages, and possible drawbacks

Quality of Cartilage Repair from Marrow Stimulation Correlates with Cell Number, Clonogenic, Chondrogenic, and Matrix Production Potential of Underlying Bone Marrow Stromal Cells in a Rabbit Model

OBJECTIVE: Previous studies have shown that intrinsic behavior of subchondral bone marrow stem cells (BMSCs) is influenced by donors and locations. To understand the variability in cartilage repair outcomes following bone marrow stimulation, we tested the hypothesis that in vivo cartilage repair correlates with in vitro biological properties of BMSCs using a rabbit model. METHODS: Full-thickness cartilage defects were created in the trochlea and condyle in one knee of skeletally mature New Zealand White rabbits (n = 8) followed by microdrilling. Three-week repair tissues were analyzed by macroscopic International Cartilage Repair Society (ICRS) scores, O’Driscoll histological scores, and Safranin-O (Saf-O) and type-II collagen (Coll-II) % stain. BMSCs isolated from contralateral knees were assessed for cell yield, surface marker expression, CFU-f, %Saf-O, and %Coll-II in pellet culture followed by correlation analyses with the above cartilage repair responses. RESULTS: In vivo cartilage repair scores showed strong, positive correlation with cell number, clonogenic, chondrogenic, and matrix production (Coll-II, GAG) potential of in vitro TGF-βIII stimulated BMSC cultures. Trochlear repair showed clear evidence of donor dependency and strong correlation was observed for interdonor variation in repair and the above in vitro properties of trochlear BMSCs. Correlation analyses indicated that donor- and location-dependent variability observed in cartilage repair can be attributed to variation in the properties of BMSCs in underlying subchondral bone. CONCLUSION: Variation in cell number, clonogenic, chondrogenic, and matrix production potential of BMSCs correlated with repair response observed in vivo and appear to be responsible for interanimal variability as well as location-dependent repair

Nanomaterial Delivery Systems for mRNA Vaccines

The recent success of mRNA vaccines in SARS-CoV-2 clinical trials is in part due to the development of lipid nanoparticle delivery systems that not only efficiently express the mRNA-encoded immunogen after intramuscular injection, but also play roles as adjuvants and in vaccine reactogenicity. We present an overview of mRNA delivery systems and then focus on the lipid nanoparticles used in the current SARS-CoV-2 vaccine clinical trials. The review concludes with an analysis of the determinants of the performance of lipid nanoparticles in mRNA vaccines