In this study, a dual-layer hollow fiber nanofiltration (NF) membrane was fabricated with an inner layer of poly(vinylidene fluoride) (PVDF) via thermally induced phase separation (TIPS), and an outer layer of cellulose diacetate (CA) via non-solvent induced phase separation (NIPS). The intermediate-treatment using dimethyl formamide (DMSO) between the two layers increased the porosity of inside surface of outer layer. The nanopore of the outside surface of outer layer was molecularly designed by controlling the dope solution composition, i.e., the polymer concentration, the co-solvent additive (acetone) ratio and TiO2 nanoparticle loading. By increasing the acetone ratio and TiO2 nanoparticle loading, the pore size became narrower and the pore size exhibited dominate effects on both filtration and separation performances. Moreover, biofouling and bacterial growth on the membrane were reduced by increasing the TiO2 nanoparticle loading. The dual-layer (CA/PVDF) hollow fiber membranes had high strengths larger than 8 MPa, Na2SO4 rejections of 90–95% and pure water permeabilities of 1–4 L m− 2 h− 1 bar− 1. The feasibility of treating RO concentrates by the resultant membrane was proven by the effective removal of total organic compounds (> 90%) and low rejection of total dissolved salts (< 60%).