Cytoplasmic delivery of functional siRNA using pH-Responsive nanoscale hydrogels

Abstract

The progress of short interfering RNA (siRNA) technologies has unlocked the development of novel alternatives for the treatment of a myriad of diseases, including viral infections, autoimmune disorders, or cancer. Nevertheless, the clinical use of these therapies faces significant challenges, mainly overcoming the charged and large nature of these molecules to effectively enter the cell. In this work, we developed a cationic polymer nanoparticle system that is able to load siRNA due to electrostatic interactions. The pH-responsiveness and membrane-disrupting ability of these carriers make them suitable intracellular delivery vehicles. In the work presented herein we synthesized, characterized, and evaluated the properties of nanoparticles based on 2-diethylaminoethyl methacrylate and tert-butyl methacrylate copolymers. A disulfide crosslinker was incorporated in the nanogels to enable the degradation of the nanoparticles in reductive environments, showing no significant changes on their physicochemical properties. The capability of the developed nanogels

Synthetic networks with tunable responsiveness, biodegradation, and molecular recognition for precision medicine applications

“…In each interval, a hydrodynamic diameter and count rate were recorded. Because count rate trends with the number of particles in solution ( 37 ), the count rate at a given time, normalized to the initial count rate, provided a measure of the degree of degradation.…”

Hydrogel‐Induced Cell Membrane Disruptions Enable Direct Cytosolic Delivery of Membrane‐Impermeable Cargo

“…[35,42] For example, Liechty et al recently demonstrated that incorporating hydrophobic moieties into a hydrogel network could significantly alter its cell membrane disruption properties. [52] This discrepancy could explain why no clear linear correlation between the DS value and FD10 delivery efficiency was observed.…”

Polymer nanocarriers for MicroRNA delivery

“…With respect to size, nanoscale materials are ideally suited for RNA delivery because they can protect RNA from degradation, extend circulation half‐life, facilitate cellular entry, and increase therapeutic index . Indeed, various nanoparticle (NP) delivery systems have shown considerable promise for the delivery of plasmid DNAs, antisense oligonucleotides, small interfering RNAs (siRNAs), and miRNAs to diseased cells in vitro and in vivo . When considering size as a design parameter for miRNA mimic delivery vehicles, it is important to note that NPs with diameters less than ∼5 nm rapidly undergo renal clearance upon intravenous administration and those with diameters greater than ~200 nm exhibit splenic filtration due to the 200–500 nm size range of interendothelial cell slits .…”

“…Polymer materials have been widely explored as tools to carry therapeutic cargo (e.g., small molecules, peptides, proteins, DNAs, siRNAs, and miRNAs) to specific tissues/cells to intervene in disease . The types of polymers that have been incorporated into delivery vehicles include poly(lactic‐ co ‐glycolic acid) (PLGA), PEG, poly‐ L ‐lysine (PLL), poly‐ L ‐arginine (PLA), PEI, and more.…”