Cationic Nanohydrogel Particles for Therapeutic Oligonucleotide Delivery

Abstract

Short pharmaceutical active oligonucleotides such as small interfering RNA (siRNA) or cytidine‐phosphate‐guanosine (CpG) are considered as powerful therapeutic alternatives, especially to medicate hard‐to‐treat diseases (e.g., liver fibrosis or cancer). Unfortunately, these molecules are equipped with poor pharmacokinetic properties that prevent them from translation. Well‐defined nanosized carriers can provide opportunities to optimize their delivery and guide them to their site of action. Among several concepts, this Feature Article focuses on cationic nanohydrogel particles as a universal delivery system for small anionic molecules including siRNA and CpG. Cationic nanohydrogels are derived from preaggregated precursor block copolymers, which are further cross‐linked to obtain well‐defined nanoparticles of tunable sizes and with (degradable) cationic cores. Novel opportunities for oligonucleotide delivery in vitro and in vivo with respect to liver fibrosis therapies will be highlighted as well as perspectives toward modulating the immune system. In general, the approach of covalently stabilized cationic carrier systems can contribute to find advanced oligonucleotide therapeutics.

α‐Mannosyl‐Functionalized Cationic Nanohydrogel Particles for Targeted Gene Knockdown in Immunosuppressive Macrophages

“…As reported earlier, a hydrophilic block ratio of ≈40% is necessary to facilitate reactive ester block copolymer self‐assembly into micellar structures in polar aprotic solvent . At the same time nanoparticles with a thicker hydrophilic shell are obtained which might have better protein repelling stealth‐like properties conferred by the polymerized MEO 3 MA monomers.…”

“…The preparation of α‐mannosyl‐functionalized cationic nanohydrogel particles (ManNP) was achieved according to the concept presented in Figure 1 …”

“…Instead of addressing this receptor by nanobodies, we took advantage of the macrophage mannose receptor's intrinsic binding affinity to mannose and developed a densely α‐mannosyl‐functionalized siRNA carrier system for effective targeting of M2 macrophages. To protect the sensitive cargo from nuclease degradation and promote cellular uptake, the polyanionic siRNA has to be loaded into a cationic nanohydrogel particle system via electrostatic interactions . Such systems can be derived from amphiphilic reactive ester block copolymers which self‐assemble into micellar structures.…”

From Polymers to Functional Biomaterials

“…The delivery of nucleic acids for gene editing in vivo provides enormous potential for a multitude of diseases, e.g. cancer (immune) therapy, or liver fibrosis, but is more demanding in terms of delivery. The carrier needs to protect the nucleic acids from degradation in the blood stream, to transport it to the target cell, to bypass the lysosomal degradation (endosomal escape), and finally to release the functional siRNA or mRNA inside the cytosol.…”

“…small interfering RNA (siRNA) or cytidine‐phosphate‐guanosine (CpG). The authors discuss synthetic concepts and their use in the modulation of the immune system …”