mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. mRNA holds the potential to revolutionize vaccination, protein replacement therapies, and the treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, 1 significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. 2 The translatability and stability of mRNA as well as its immunostimulatory activity are the key factors to be optimized for specific therapeutic application. 3 Increased translation and stability can be affected by many regions of the RNA. mRNA 5 0 and 3 0 UTRs are responsible for recruiting RNA-binding proteins and microRNAs, and they can profoundly affect translational activity. 2,4 The modification of rare codons in protein-coding sequences with synonymous frequently occurring codons, so-called codon optimization, can result in order-of-magnitude changes in expression levels. 5,6 Modification of the 5 0 mRNA cap can also enhance mRNA translation by inhibiting RNA decapping and improving resistance to enzymatic degradation. 7 Chemical modification of RNA bases can be used to modify mRNA immunostimulatory activity. 8,9 The importance of immunostimulation can depend on the application, 10 and, in some cases, it may actually improve performance, as in the case of vaccines. 11Finally, methods and vehicles for intracellular delivery remain the major barrier to the broad application of mRNA therapeutics. 12 With some exceptions, the intracellular delivery of mRNA is generally more challenging than that of small oligonucleotides, and it requires encapsulation into a delivery nanoparticle, in part due to the significantly larger size of mRNA molecules (300-5,000 kDa, 1-15 kb) as compared to other types of RNAs (small interfering RNAs [siRNAs], 14 kDa; antisense oligonucleotides [ASOs], 4-10 kDa). 10,13 In this review, we discuss the challenges for clinical translation of mRNAbased therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination. Materials for mRNA Delivery Structural Aspects of Material DesignAmong the many barriers to function, mRNA must cross the cell membrane in order to reach the cytoplasm (Figure 1). The cell me...

The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino-polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino-alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure-activity parameters crucial for efficient transfection are established and APE-LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE-LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo-jetPEI. Adopting tertiary amino-alcohols to initiate ROP of lactones allows to control polymer molecular weight and obtain amino-polyesters with narrow molecular weight distribution, exhibiting batch-to-batch consistency. All of which highlight the potential for clinical translation of APEs for systemic mRNA delivery and demonstrate the importance of employing controlled polymerization in the design of new polymeric nanomaterials to improve in vivo nucleic acid delivery.

Bryostatin 1 is a marine natural product that is a very promising lead compound due to the potent biological activity it displays against a variety of human disease states. We describe herein the first total synthesis of this agent. The synthetic route adopted is a highly convergent one in which preformed and heavily functionalized pyran rings A and C are united by "pyran annulation": the TMSOTf promoted reaction between a hydroxy allylsilane appended to the A ring fragment and an aldehyde contained in the C ring fragment, with concomitant formation of the B ring. Further elaborations of the resulting very highly functionalized intermediate include macrolactonization and selective cleavage of just one of five ester linkages present.Bryostatin 1 is a now well-known natural product originally isolated by Pettit and coworkers from the marine organism Bugula neritina. 1 Since that time, other members of this family have been isolated such that some 20 members are now known. 2 It has also been established that the true source of the bryostatins is not actually Bugula neritina, but rather a bacterial symbiont. 3 Interest in the bryostatins, and bryostatin 1 in particular, has been intense due to the wide range of potent bioactivity associated with bryostatin 1. Bryostatin 1 has shown activity against a range of cancers, and has also shown synergism with established oncolytic agents such as Taxol®. 4 This has led to the use of bryostatin 1 in numerous clinical trials for cancer, despite the absence of any renewable supply for this compound at present. In addition, bryostatin 1 has shown promising activity relevant to a number of other diseases and conditions, including diabetes, 5 stroke, 6 and Alzheimer's disease. 7 A clinical trial for Alzheimer's disease is commencing. 8 This wide range of promising potential indications for bryostatin 1 becomes more understandable when it is recognized that at least one mechanism for function of this agent involves activity on protein kinase C (PKC) isozymes and on other C1 domain containing proteins. 9 These signaling proteins are known to regulate some of the most critical cellular processes and properties, including proliferation, differentiation, motility and adhesion, inflammation, and apoptosis. 10 Given this backdrop, it is not surprising that synthetic activity directed towards the bryostatins has been intense. What is surprising, perhaps, is that bryostatin 1 itself has not been previously synthesized, while other members of the family have been prepared. Previous total syntheses include those of bryostatin 7 (2, by Masamune), bryostatin 2 (3, by Evans), bryostatin 3 (4, by Yamamura), and bryostatin 16 (5, by Trost). In addition, Hale has described a formal synthesis of bryostatin 7, and Trost has recently reported a synthesis of C20-epi-bryostatin 7. 11 * keck@chem.utah.edu .Supporting Information Available Experimental procedures and spectral data. This material is available free of charge via the Internet at http://pubs.acs.org. Another very important aspect...

‘OH’ no you don't: The title compound 1 has been synthesized and evaluated for biological function. Molecular modeling of bryostatin 1 with the C1 domain of protein kinase C  δ indicates that the C9OH of bryostatin 1 makes a hydrogen‐bonding contact to the protein. Despite the absence of the hydrogen‐bonding contact for 1, it displays bryostatin‐like biological effects in four assays using either U937 leukemia cells or prostate LNCaP cells.