Device surface-functionalized ac-SDKP nanoassemblies accelerate endothelial recovery through dual anti-inflammatory...

While stents are cornerstone treatments for atherosclerosis, in-stent restenosis remains a challenge. Engineering stent surfaces with specific biochemical signals can prevent this by promoting the crucial and timely regeneration of the endothelium. In this work, Ac-SDKP (N-Acetyl-Ser-Asp-Lys-Pro), an anti-inflammatory and endothelial homeostasis-regulating peptide, was incorporated into a blood-compatible PAMAM (poly-amidoamine) platform to yield pro-endothelial repair nanoassemblies. Ac-SDKP nanoassemblies attenuated macrophage activity and TNF α secretion, as well as neutrophil myeloperoxidase release. Simultaneously, the modified surface enhanced endothelial cell (EC) activity, proliferation and protection. The immobilized Ac-SDKP suppressed both extrinsic (caspase 8 pathway) and intrinsic (cytochrome c pathway) apoptotic signal, along with caspase-1-mediated inflammatory death, while also activating PI3K pathway to exert an anti-death effect. Furthermore, the nanoassemblies also suppressed the transmission of EC dysfunction signals by inhibiting the IKKα-RELB pathway, including monocyte chemoattractant protein-1 (linked to inflammation) and tissue factor (promoting coagulation), thereby helping to protect endothelial function. Collectively, this novel modification strategy promoted endothelial regeneration, suppressed neointimal hyperplasia, and reduced inflammatory cell infiltration in Sprague Dawley rats. In summary, constructing Ac-SDKP nanoassemblies on a PAMAM framework promotes endothelial recovery through anti-inflammatory and endothelial protection mechanisms, offering a potential approach for preventing post-implantation complications.