Stable and bioactive material—tissue interface (MTF) basically determines the clinical applications of biomaterials in wound healing, sustained drug release, and tissue engineering. Although many inorganic nanomaterials have been widely explored to enhance the stability and bioactivity of polymer-based biomaterials, most are still restricted by their stability and biocompatibility. Here we demonstrate the enhanced bioactivity and stability of polymer-matrix bio-composite through coupling multiscale material—tissue interfacial interactions with atomically thin TiO
2
nanosheets. Resin modified with TiO
2
nanosheets displays improved mechanical properties, hydrophilicity, and stability. Also, we confirm that this resin can effectively stimulate the adhesion, proliferation, and differentiation into osteogenic and odontogenic lineages of human dental pulp stem cells using
in vitro
cell—resin interface model. TiO
2
nanosheets can also enhance the interaction between demineralized dentinal collagen and resin. Our results suggest an approach to effectively up-regulate the stability and bioactivity of MTFs by designing biocompatible materials at the sub-nanoscale.
Electronic Supplementary Material
Supplementary material (further details of fabrication and characterization of TiO
2
NSs and TiO
2
-ARCs, the bioactivity evaluation of TiO
2
-ARCs on hDPSCs, and the measurement of interaction with demineralized dentin collagen) is available in the online version of this article at 10.1007/s12274-022-5153-1.