Surface functionalization of multilayer nanoparticles with hyaluronic acid or alternative polymers: Effects on cellular uptake and re-epithelialization in a human ex vivo wound model

Prolonged inflammation and microbial infections are the main issues that slow down the healing process. To improve wound repair, remarkable advances in nanotechnology have enabled the development of nanomaterials with multifunctional features, including antibacterial, anti-inflammatory, and pro-angiogenic properties. In this study, the layer-by-layer (LbL) technique is used to precisely customize the surface of nine multilayer nanoparticles (NPs) with the aim of exploring the influence of the surface composition on wound healing. LbL-NPs are functionalized with different polymers exhibiting potential wound healing properties. Among the studied polymers, surface functionalization with polysaccharides such as hyaluronic acid (HA), dextran sulfate (DEX), trimethyl chitosan (TMC), and fucoidan (FCD) promotes the uptake of multilayer nanoparticles by human keratinocytes and favor tissue repair in a human ex vivo wound model. Around 80 % of cells internalize LbL-HA and LbL-TMC NPs in 4 h, likely by interacting with cell surface polysaccharide receptors. Moreover, it is demonstrated that, compared to the free HA, LbL-HA NPs enable a significant improvement in the re-epithelialization and neovascularization in a human ex vivo model, which is supported by an increased expression of both keratin 17 and CD31 (p < 0.0001). These findings underscore the potential of surface functionalized LbL-NPs as highly engineered biocompatible drug delivery systems with inherent wound healing properties.