NIR-responsive smart hydrogel incorporating LF-decorated nanosheets recalibrating the immune-vascular-osteogenic microenvironment for enhanced bone regeneration

Abstract Critical-sized bone defects possess inherently limited self-healing potential, posing a persistent challenge in clinical bone repair. In recent years, numerous hydrogel systems have been developed for bone defect repair and have made remarkable progress, but most lack programmable responsiveness to microenvironmental cues, hindering precise drug delivery and dynamic regulation during bone reconstruction. Here, we developed a near-infrared (NIR)-responsive smart hydrogel (GP/MPL) based on GelMA and PEGDA, incorporating polydopamine-coated Ti3C2 MXene nanosheets decorated with lactoferrin (LF), with an average interlayer spacing of 1.88 nm to enhance bioactivity. Upon 808 nm NIR irradiation, the hydrogel temperature rises to approximately 42 °C, enabling targeted LF release. In vitro, the multifunctional hydrogel exhibited inhibition rates of 88.6 ± 2.3% and 92.7 ± 0.7% against Escherichia coli and Staphylococcus aureus, respectively, while dynamically regulating reactive oxygen species (ROS) scavenging, immunomodulation, angiogenesis, and osteogenesis. Furthermore, in vivo experiments demonstrated that the smart hydrogel promoted vascularized bone regeneration in critical-sized defects through activation of the HIF-1α/VEGF and PI3K/Akt signaling pathways. These promising outcomes demonstrate the capacity of the GP/MPL smart hydrogel as an advanced strategy to efficiently promote bone regeneration by recalibrating the microenvironment. Graphical Abstract