Vascular bypass grafting is a routine treatment for cardiovascular diseases; however, ~50% of bypass grafts fail in the few years following surgery due to aberrant cellular responses at the suture sites. To address this problem, we recently focused on designing new and highly tunable light-based strategies to deploy nucleic acids with control at cellular length scales. Lipid-small interfering RNA (siRNA) complexes (lipoplexes) were modified with stimuli-responsive polymers to gain spatiotemporal control over gene knockdown in human primary aortic adventitial fibroblasts (AoAFs), which enabled the elucidation of the functional roles of IL1β and CDH11 in improving vascular healing. Our previous work established the beneficial properties of our mPEG-b-poly(5-(3-(amino)propoxy)-2-nitrobenzyl methacrylate) [mPEG-b-P(APNBMA)] block copolymer system for vascular applications, including high stability and the capacity to locally regulate the extent of protein silencing on cellular length scales. Additionally, the precisely controlled nature of the system allows for accurate predictions of siRNA dosing regimens that facilitate gene knockdown over clinically-relevant timescales associated with adventitial remodeling (one week). We exploited these characteristics through the formulation of hybrid nanocarriers that mediated on-demand, spatially-controlled knockdown of IL1β and CDH11 in AoAFs to ≤ 5% of their initial levels following treatment with a photo-stimulus. The silencing of IL1β on its own significantly reduced myofibroblast differentiation and proliferation, whereas CDH11 silencing on its own had only a moderate effect. Subsequently, kinetic modeling approaches were used to design dosing regimens that fully silenced IL1β and/or CDH11 together, over sustained time periods. Complete attenuation of TGF-β1-induced myofibroblast differentiation was achieved by simultaneously silencing IL1β and CDH11 for one week, the timescale relevant to adventitial remodeling. Thus, we uncovered synergistic functional roles of IL1β and CDH11 in AoAFs and showed that sustained knockdown of these genes is a viable method for mitigating fibrotic responses. In the longer term, the photo-sensitive lipid-polymer nanocomplexes offer a unique opportunity to locally regulate fibrotic conditions and improve healing following cardiovascular surgery.

Attenuation of maladaptive responses in aortic adventitial fibroblasts through stimuli-triggered siRNA release from lipid-polymer nanocomplexes

256th National Meeting (2018)

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