CO enhances agomir transfection under pathological conditions to inhibit MMP overexpression

Cellular uptake of exogenous nucleic acids is inhibited in pathological tissues accompanied by excessive expression of matrix metalloproteinases (MMPs). We show that CO, as a regulator of membrane function, can reactivate uptake of agomir (Ago) in pathological condition via RAB5-mediated endocytic pathway. Herein, a responsive nanoparticle-crosslinked injectable hydrogel (CO-Ago gel) was engineered as a prototype for co-delivering CO and Ago to inhibit MMP overexpression in accordance with the disease severity. Compared to a typical matrix-enhanced gene therapy (Ago gel), CO-Ago gel significantly promoted Ago uptake, achieving an order of magnitude improvement of targeted gene expression under pathological conditions (11.2-fold for cardiomyocyte and 15.3-fold for primary fibroblasts). The therapeutic effect of CO Ago gel on MMP overexpression was assessed in rat models of myocardial ischemia reperfusion and diabetic skin wound healing. The results suggest CO-enhanced transfection could contribute to the development of next-generation adjuvants for gene-based therapies and vaccines in vivo. & COPY; 2023 Elsevier Ltd. All rights reserved.

Automated summary

CO can reactivate uptake of agomir in pathological conditions via RAB5-mediated endocytic pathway, and a responsive nanoparticle-crosslinked injectable hydrogel (CO-Ago gel) was designed to co-deliver CO and Ago to inhibit MMP overexpression. Compared to a typical matrix-enhanced gene therapy (Ago gel), CO-Ago gel significantly improved the uptake of Ago, achieving a several-fold enhancement of targeted gene expression under pathological conditions. The therapeutic effect of CO-Ago gel on MMP overexpression was assessed in rat models of myocardial ischemia reperfusion and diabetic skin wound healing, suggesting its potential in gene-based therapies and vaccines in vivo.