OBJECTIVES: The effects of different interface treatments on the interfacial bonding of inorganic fillers in composite resins and the overall performance of the composite resins were investigated. METHODS: Synthetic mussel derivatives (N-3,4-dihydroxyphenethyl methacrylamide, DMA) were used as primers to treat the inorganic filler bonding interfaces, and the effects of different concentrations of DMA on the shear strength of the bonding interface were tested. Silica nanoparticles were coated on the surface of the filler via the sol-gel growing, and the mechanical properties and aging resistance of the composite resin were tested. RESULTS: The DMA primer concentration of 0.1-1mg/mL substantially improved the shear strength of the bonding interface, and combined with the coating of silica nanoparticles, it improved the compressive strength and toughness of the aged composite resin. CONCLUSIONS: This study indicated that the use of the DMA primer and coated silica nanoparticles increased the bonding strengths and stabilities at the organic-inorganic interfaces, and also improved the mechanical strengths and durability of the composite resins. CLINICAL SIGNIFICANCE: Fortified with DMA and silica nanoparticles, the composite resin exhibits great bonding strength, hydrolysis resistance, and toughness. This innovation could stabilize the resin for long-term and lower the risk of secondary caries. This study paves the way for the clinical application of novel resins to prevent secondary caries in the future.