ABSTRACT
mRNA vaccines open promising avenues for overcoming a variety of diseases due to their high therapeutic utilities, rapid growth capacities, and safe administration potentials. With the emergence of COVID-19, the use of mRNA vaccines has become even more widespread and far-reaching. However, for mRNA to be delivered to target cells and tissues, several obstacles must be overcome. For instance, naked mRNAs get easily and hastily degraded by ribonucleases in tissues and the bloodstream, and since mRNAs are large and polyanionic molecules, they cannot passively diffuse across cell membranes. Even though mRNAs are internalized by APCs, they must be able to reach the cytoplasm and escape endo-lysosomal traffic. Therefore, distinctive transport systems for efficient encapsulation of mRNAs using nanocarrier systems are required to ensure their delivery to cells’ cytoplasm. At this point, non-viral gene delivery systems such as polymers and lipids come to the fore, in which they can overcome the biological barriers and provide efficient delivery of mRNAs. Recently, mRNA vaccines have been used as a powerful weapon against COVID-19 pandemic which has affected the whole world since December 2019. This was clear by the emergence of Pfizer-BioNTech and Moderna vaccines, which offered mRNA vaccines with auspicious treatment abilities. A variety of carrying candidates have been utilized in such vaccines as polymers, metal nanoparticles, as well as LNPs, which each comes with its cons and pros in delivering mRNA. All of these mentioned points will be clarified and discussed in detail in this review paper.
ABSTRACT
One option to improve tissue regeneration is the use of growth factors. As a promising alternative to recombinant protein therapy, gene therapy allows local and sustained release of growth factors. This moderate and constant release is more suitable for regenerative processes compared to administration of high protein doses. Exogenous growth factors are produced by cells in situ;such highly bioactive amounts of growth factors are produced directly at the defect site, thereby highly limiting adverse off-target effects. Targeted research areas include (combinatorial) gene therapy approaches for bone/musculoskeletal tissue regeneration in vivo and ex vivo. Amongst them, new techniques such as viral and non-viral gene delivery systems, next-generation therapeutical DNA vectors for example with decreased immunogenicity, enhanced bioactivity of growth factor and enhanced gene expression. Beside DNA based gene therapy also mRNA based technologies are increasingly used and becoming popular by Covid vaccination successes. Increasing records of clinical success in the last years have constantly improved awareness of gene therapy, strengthening the enthusiasm of the community for novel and effective treatment methods providing the needed momentum for further developments.
ABSTRACT
Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology-encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes.