Delivery of MiRNA-92a Inhibitor Using RP1-Linked Peptide Elicits Anti-Inflammatory Effects in an Acute Lung Injury Model

Abstract

Acute lung injury (ALI) is an inflammatory lung disease. miRNA-92a (miR92a) is induced in the lungs of ALI patients and mediates inflammatory reactions. In this study, a RP1-linked R3V6 (RP1R3V6) peptide was synthesized and evaluated as a carrier of anti-microRNA-92a oligonucleotide (AMO92a) into the lungs of an ALI animal model. In addition to the carrier function, the RP1-linked peptide can have anti-inflammatory effects in the lungs, since RP1 is an antagonist of the receptors for advanced glycation end-products (RAGEs). In a gel retardation assay, the RP1R3V6 peptide formed a spherical complex with AMO92a. In an in vitro delivery assay to L2 rat lung epithelial cells, RP1R3V6 had a lower AMO92a delivery efficiency than R3V6 and polyethyleneimine (PEI25k; 25 kDa). However, RP1R3V6 had an additional anti-inflammatory effect, reducing tumor necrosis factor-α (TNF-α) in lipopolysaccharide-activatedmacrophage cells. With the combined effects of AMO92a and RP1, the RP1R3V6/AMO92a complex reduced the miR92a level more efficiently than did the R3V6/AMO92a and PEI25k/AMO92a complexes. The RP1R3V6/AMO92a complex was administered into the lungs of ALI animals by intratracheal instillation. As a result, the expression of phosphatase and tensin homolog, a target of miR92a, was increased in the lungs. Furthermore, the RP1R3V6/AMO92a complex decreased the TNF-α and interleukin-1β (IL-1β) levels more efficiently than did the PEI25k/AMO92a and R3V6/AMO92a complexes, decreasing the damage in the lungs. These results suggest that RP1R3V6 is a useful carrier of AMO92a and has anti-inflammatory effects in an ALI animal model.

Hybrid nanoparticles with cell membrane and dexamethasone-conjugated polymer for gene delivery into the lungs as therapy for acute lung injury

“…Lung tissues were extracted in reporter lysis buffer as described previously. 12 The extracts were analyzed using TNF-α, IL-6, and IL-1β ELISA kits.…”

“…9 In addition, inhibition of microRNA (miR)-7b and miR-92a using antisense oligonucleotides improved inflammation in lipopolysaccharide (LPS)-induced ALI. 11,12 Despite successful therapeutic gene delivery in ALI animal models, the absence of efficient and safe gene carriers remains an obstacle to the application of gene therapy to patients with ALI. Delivery carriers have been developed and evaluated for gene delivery into the lungs.…”

Pulmonary Delivery for miRs: Present and Future Potential

“…Zhuang et al [172] recently evaluated the intratracheal administration of a miR-92a inhibitor to treat acute lung injury. The anti-miR-92a (AMO92a) oligonucleotide was administered with an RP1-linked R3V6 peptide, which also has anti-inflammatory effects in the lungs as RP1 is an advanced glycation end-products receptor antagonist.…”

“…miR-155 agomir and antagomir Allergic rhinitis Saline [193] miR-127 Lung Inflammation Chemically modified nucleic acids and LNA in PBS [194] miR-135a Allergic rhinitis Chemically modified nucleic acids in saline [195] Allergic rhinitis Lentiviruses [196] miR-410 Airway inflammation Chemically modified nucleic acids in water [197] miR-223-3p Allergic rhinitis Saline [198] Let-7i Traumatic Brain Injury Water [199] miR-203 antagomir Chronic epilepsy Chemically modified nucleic acids in PBS [200] Anti-miR-134 Epilepsy seizures LNA and chemically modified nucleic acids in water [201] miR-124 Ischemic brain injury RVG29-modified PLGA-PEG nanoparticles. Nucleic acids were premixed with spermidine [202] Anti-miR-21 Glioblastoma Self-assembled nanoparticles of RAGE-antagonist peptide and nucleic acids [203] miR-219a-5p Multiple sclerosis DSPC liposomes, PLGA nanoparticles, and extracellular vesicles comparison [49] Anti-miR-210 Hypoxic-ischemic brain injury LNA in saline [204] Anti-miR-143/145 Pulmonary Hypertension LNA in PBS [183] Anti-miR-223-3p SARS-CoV-2/lungs LNA [205] miR-29 Allergic rhinitis Saline [206] miR-146a Temporal lobe epilepsy Water [207] Anti-miR-155 Allergic airways disease Chemically modified nucleic acids [186] Anti-miR-489 Bronchopulmonary dysplasia LNA in water [182] Anti-miR-126 Allergic airways disease Chemically modified nucleic acids in saline [185] Anti-miR-218-5p Chronic obstructive pulmonary disease PBS [184] miR-2392 SARS-CoV-2/lungs Peptide nucleic acid in nanoparticles (nanoligomer SBCoV207) [187] miR-101 Pulmonary fibrosis Adenoviruses [208] Intratracheal Anti-miR-92a Acute Lung Injury Model RP1-linked R3V6 peptide complexed with nucleic acids [172] Anti-miR-21 Lung fibrosis PBS [169] miR-146a…”