Bioengineered titanium implants functionalized with aptamer-valproic acid conjugates orchestrate macrophage programming and mesenchymal stem cell homing for improved osseointegration.

Conventional titanium implants often exhibit limited bioactivity, failing to adequately modulate the immune response and promote endogenous regeneration, which leads to suboptimal osseointegration. To address this, we developed a multifunctional implant (NTP/Apt-VPA) by conjugating Apt19s-an mesenchymal stem cell (MSC)-specific aptamer-with valproic acid (VPA), anchored onto a polydopamine-coated TiO2 nanotubular surface. The NTP/Apt-VPA implant demonstrated exceptional capabilities in scavenging reactive oxygen species, programming macrophages toward the regenerative M2 phenotype, and enhancing the recruitment and osteogenic differentiation of MSCs. Through comprehensive in vitro and in vivo assessments, as well as RNA sequencing analysis, we observed that the modified implant was associated with accelerated early inflammation resolution, enhanced stem cell homing, and activation of key osteogenic pathways, including PI3K/AKT and MAPK signaling. This study presents a bioengineering strategy that aims to synchronize immunomodulation with osteogenesis through an Apt19s-VPA conjugate, which may offer a promising platform for enhancing implant osseointegration.