OBJECTIVE: To investigate the modulatory effects of four proanthocyanidin-DESIGNERS (PAC-DESIGNERs) on the long-term bond strength of the resin-adhesive interface, the degree of conversion of resin monomers, the chemical-mechanical properties of dentin matrix, and cell biocompatibility. METHODS: Standardized formulations of PACs with a dominant degree of polymerization - DP (trimers: PM-AB and CV-AB; tetramers: PM-ABA and CV-ABB) were prepared from two sources of AB-Type PACs using a DESIGNER approach. Resin-dentin interface was assessed after 24 hours and 1 year using a microtensile bond strength (µTBS) test. The degree of conversion (DC) of resin monomers and chemical analysis of the dentin matrix were analyzed by ATR-FTIR spectroscopy. The viscoelastic properties of the dentin matrix were assessed by dynamic mechanical analysis (DMA). Cell viability was analyzed using a 3D cell culture model. Data analysis using two- and one-way ANOVA and post-hoc tests (α = 0.05). RESULTS: All PAC-DESIGNER biomodulation increased the µTBS when compared to control (p < 0.05), regardless of source, DP, and aging. The DC of resin adhesive was not negatively impacted, and an increase in DC was observed with the incorporation of PM-AB and PM-ABA DESIGNERs (p < 0.05). PAC-DESIGNER treatment also increased the dentin matrix complex modulus (153-79 MPa) and storage modulus (151-78 MPa) when compared to control (∼9 MPa, p < 0.05). All DESIGNERs decreased the intensity of amide II/CH(2) ratio; a decrease in the amide III/CH(2) ratio was observed for CV-ABB (p < 0.05). Moreover, PAC-DESIGNERs exhibited good cell biocompatibility and healthy cell morphology. SIGNIFICANCE: All PAC-DESIGNERs optimized the dentin-resin µTBS. The different molecular structures played a modulatory role in the chemical-mechanical properties of the dentin matrix, the degree of conversion of adhesive, and cell biocompatibility.