Targeted Dual Small Interfering Ribonucleic Acid Delivery via Non‐Viral Polymeric Vectors for Pulmonary Fibrosis Therapy

Abstract

Inhibiting the myofibroblast differentiation of lung‐resident mesenchymal stem cells (LR‐MSCs) is a promising yet challenging approach for pulmonary fibrosis (PF) therapy. Here, micelles formed by a graft copolymer of multiple PEGs modified branched polyethylenimine are used for delivering runt‐related transcription factor‐1 (RUNX1) small interfering RNA (siRNA) (siRUNX1) to the lung, aiming to inhibit the myofibroblast differentiation of LR‐MSCs. LR‐MSC targeting is achieved by functionalizing the micelle surface with an anti‐stem‐cell antigen‐1 antibody fragment (Fab′). Consequently, therapeutic benefits are obtained by successful suppression of myofibroblast differentiation of LR‐MSCs in bleomycin‐induced PF model mice treated with siRUNX1‐loaded micelles. Furthermore, an excellent synergistic effect of PF therapy is achieved for this micelle system loaded siRUNX1 and glioma‐associated oncogene homolog‐1 (Gli1) small interfering RNA (siGli1), a traditional anti‐PF siRNA of glioma‐associated oncogene homolog‐1. Hence, this work not only provides RUNX1 as a novel PF therapeutic target, but also as a promising dual siRNA‐loaded nanocarrier system for the therapy of PF.

Pulmonary delivery of siRNA against acute lung injury/acute respiratory distress syndrome

“…The developed carrier achieved remarkable antifibrotic effects and successfully suppressed the development of bleomycin-induced PF in murine model 169 . The same PMs loaded with siRNA against runt-related transcription factor-1 and decorated with an anti-stem-cell antigen-1 antibody could successfully inhibit PF in mice by preventing the differentiation of lung resident mesenchymal stem cells into myofibroblast 170 .…”

Polymer nano-systems for the encapsulation and delivery of active biomacromolecular therapeutic agents

“…Controlled release of plasmidDNA 66 Absence of chemical modification of the drug Limited encapsulation efficiencies Targeted delivery of siRNA 67 Variety of morphologies and architectures High risk of dissociation in blood mRNA delivery (animal study) 68 High protection Polymersome delivery of the SARS-CoV-2 spike protein (preclinical trials) 69 Nanoparticle/ nanogel/ nanocapsule Physical encapsulation Protein encapsulation 70 Absence of chemical modification of the drug Risk of denaturation due to crosslinking reactions involved Enzyme nanocapsules 71 High protection Delivery and controlled release of deoxyribonuclease I 72 High stability Vaccine development based on nanogel protein delivery (animal study) 73 Easy incorporation of smart units Iduronate 2-sulfatase delivery with PLGA nanoparticles (preclinical testing) 74 Controlled release harness the immune stimulatory benefits of the protein to increase the anti-tumor responses while minimizing undesired therapeutical side effects. 84 In this PEG-functionalized form, the IL2 is inactive and a biological prodrug.…”

“…In such a case, the hydrophobic segment is the complex of the ionomer block of Fig. 5 (a) Schematic representation of polymeric micelles and polymersomes, (b) scheme of the formation of siRNA-loaded micelles via the assembly of negatively charged siRNA and the positively charged block copolymers PEI-g(20)-PEG-MAL, followed by the conjugation of a stem cell antigen 1 antibody (Anti-sca 1 Fab 0 ) for the targeting of lung mesenchymal stem cells and Alexa 647 fluorescence images of the organs of a mouse administrated with Fab 0 -conjugated Micelle, 67 (c) self-assembly of polyNIPAM-polyDEA block copolymers into a polymersome with a ''boarding gate'' and a ''release gate'', 66 the copolymer and the BTA, which is then surrounded by the neutral hydrophilic block. The neutralization of the charge of the block copolymers by a charged payload induces the required amphiphilicity for the micelle assembly.…”

“…5b). 67 Such a treatment aims at inhibiting the myofibroblast differentiation of lung-resident mesenchymal stem cells for pulmonary fibrosis therapy. The copolymers of cationic PEI grafted with maleimide-PEG (PEI-g-PEG-Mal) successfully encapsulated the siRNA and their surface was further modified with a stem cell antigen 1 antibody (anti-Sca1 Fab 0 ) to target mesenchymal stem cells in the lung (Fig.…”

“…Fig.5(a) Schematic representation of polymeric micelles and polymersomes, (b) scheme of the formation of siRNA-loaded micelles via the assembly of negatively charged siRNA and the positively charged block copolymers PEI-g(20)-PEG-MAL, followed by the conjugation of a stem cell antigen 1 antibody (Anti-sca 1 Fab 0 ) for the targeting of lung mesenchymal stem cells and Alexa 647 fluorescence images of the organs of a mouse administrated with Fab 0 -conjugated Micelle,67 (c) self-assembly of polyNIPAM-polyDEA block copolymers into a polymersome with a ''boarding gate'' and a ''release gate'',66 (d) DLS measurements of crosslinked polymersomes at different temperatures, 66 (e) in vivo transfection and expression of plasmid DNA delivered by polymersomes and controls (experiments conducted with triplicates). 66 (b) Reprinted with permission from ref.…”