Nanoparticle−Hydrogel Sustained-Release System for the Delivery of si-NEDD4: A Promising Strategy for the Treatment of Keloids

Keloids (KD) are a type of fibrous proliferative skin disease characterized by excessive collagen fiber proliferation due to dysregulation of collagen synthesis and metabolism during the healing process of skin wounds. KD often grows uncontrollably beyond the wound area and presents tumor-like features, severely affecting the physical and mental health of patients. KD has a high rate of recurrence after clinical treatment. Previous studies have demonstrated that NEDD4 plays a key role in scar formation by regulating various signaling pathways. In this study, we observed a significant increase in the expression of NEDD4 in human KD, further suggesting that it may play an important role in the pathogenesis of KD. Therefore, this study aims to explore whether inhibiting NEDD4 expression can suppress keloid growth. To achieve sustained inhibition of NEDD4 expression, we developed a nanoparticle-hydrogel sustained-release system for the delivery of NEDD4 siRNA (si-NEDD4). <i>In vitro</i>, the inhibition of NEDD4 expression in KD cells resulted in a significant suppression of proliferation and migration as well as a substantial reduction in collagen expression and the phosphorylation levels of ERK1/2 and P38. Furthermore, there was a significant upregulation of apoptosis markers. <i>In vivo</i> study demonstrates that the siRNA@NPs-hydrogel system significantly reduced the weight of the xenograft KD tissue, substantially lowered the expression of NEDD4, Col1a1, and Col3a1, and significantly induced the apoptosis level. Overall, our findings suggest that local delivery of si-NEDD4 via a nanoparticle-hydrogel sustained-release system may represent a promising approach for the treatment of KD.