SiRNA Delivery from an Injectable Scaffold for Wound Therapy

Abstract

Aberrant overexpression of proinflammatory molecules is believed to be a key mediator in the formation of chronic skin wounds, and the inhibition of these signals may be an effective therapeutic strategy to promote healing. Small interfering RNA (siRNA) can provide gene-specific silencing and may present a safe and effective route for knockdown of inflammatory or other target proteins in chronic skin wounds. siRNA suffers from delivery barriers in vivo such as susceptibility to degradation, membrane impermeability, and transient activity. Therefore, a delivery strategy that stabilizes siRNA, provides intracellular (cytoplasmic) delivery, and produces temporally sustained activity is needed. The novel approach described combines pH-responsive, siRNA-loaded nanoparticles into a biodegradable polyurethane (PUR) scaffold and presents a promising platform for effective, local silencing of deleterious genes in nonhealing skin wounds. The siRNA delivery barriers have been overcome using a nanoparticulate carrier that protects siRNA and responds to pH gradients in the endo-lysosomal pathway to mediate cytosolic delivery. Nanoparticle incorporation into a biodegradable PUR scaffold provides a means for controlling the delivery kinetics of siRNA-loaded carriers. Furthermore, the PUR is injectable, making it feasible for clinical use, and provides a porous tissue template for cell in-growth during tissue regeneration and remodeling. This local siRNA delivery platform can be tuned to optimize release kinetics for specific pathologies. siRNA may provide a new class of biologic drugs that will outperform growth factor approaches, which have shown only moderate clinical success. The new platform presented here may provide clinicians with an improved option for wound care.