Cocktail Polyplexes With Synchronous Flightless I siRNA and Nitric Oxide Release for Potential Chronic Wound Healing

Abstract Chronic wounds are one of the health challenges threatening human life. In these wounds, overexpression of some types of cytoskeletal actin‐remodeling proteins including Flightless I (Flii) can often lead to severe skin scarring. Herein, arginine functionalized poly(β‐amino ester)s are synthesized to develop polyplexes with alginate for delivery of Flii siRNA. This approach results in forming polyplexes with distinct features, such as tunable zeta potential, particle size, polydispersity, and arginine conjugation level. It is demonstrated that the uptake of arginine functionalized poly(β‐amino ester)/alginate particles is composition‐dependent for various cell types including J774.1 macrophages and BJ fibroblasts. Such polyplexes trigger nitric oxide release by macrophages enhancing the expression of anti‐inflammatory genes while diminishing the expression of pro‐inflammatory markers and demonstrating its immunomodulatory properties. Flii siRNA loaded particles provide condensed siRNA into the core‐shell polyplex and exhibit controlled release of Flii siRNA over 24 h. The uptake rate of this polyplex by macrophages and fibroblasts is higher than that of a commercial gene carrier (Lipofectamine 2000), knocking down the in vitro Flii gene expression (1.3‐fold). The increased BJ fibroblast proliferation and higher expression of collagen I (COL I) show the suitability of these polyplexes for wound healing.