This study aimed in evaluating the effects of two experimental resin bonding systems containing conventional Bioglass 45S5 (BAG) or Zinc-polycarboxylated bioactive glass (BAG-Zn) micro-fillers on the resin-bonded dentine interface after storage in a simulated body fluid solution (SBFS). Three resin bonding systems were formulated: Resin-A: (BAG containing); Resin-B; (BAG-Zn containing); Resin-C (no filler). The ability of the experimental resins to evoke apatite formation was evaluated using confocal Raman spectroscopy. Acid-etched dentine specimens were bonded, and prepared for AFM/nano-indentation analysis in a fully-hydrated status to evaluate the modulus of elasticity (Ei) and hardness (Hi) across the interface at different SBFS storage periods. Further resin-dentine specimens were tested for microtensile bond strength after 24 h or 3 months of SBFS storage. SEM examination was performed after de-bonding and confocal laser microscopy was used to evaluate the ultramorphology of the interfaces and micropermeability. The resin A and B showed a consistent presence of apatite (967 cm(-1)), reduced micropermeability within the resin-dentine interface and a significant increase of the Ei and Hi along the bonded-dentine interface after prolonged SBFS storage. Bond strength values were affected by the resin system (P < 0.0001) and by storage time (P < 0.0001) both after 24 h and 3 months of SBFS storage. In conclusion, resin bonding systems containing bioactive fillers may a have therapeutic effect on the nano-mechanical properties and sealing ability of mineral-depleted resin-dentine interface.