A novel pH-sensitive, amphiphilic and biodegradable copolymer brush, methoxy poly(ethylene glycol)-block-(polycaprolactone-graft-poly(methacrylic acid)) (mPEG-b-(PCL-g-PMAA)), was developed for NPs for the oral delivery of hydrophobic drugs. The copolymer brush was synthesized by combining ring-opening polymerization (ROP) and atom transfer radical polymerization (ATRP), followed by selective hydrolysis. The structure and composition of the copolymer and its precursors were characterized by ¹H-NMR, FT-IR and GPC. The critical micelle concentrations (CMC) of mPEG-b-(PCL-g-PMAA) in aqueous medium were determined to be 6.8 × 10⁻⁴ and 9.6 × 10⁻⁴ mg mL⁻¹. The copolymer could self-assemble into NPs in aqueous solution with an average size of 104–129 nm, determined by DLS. The morphology of the NPs was spherical, as observed by TEM. The zeta potentials of the NPs were about −25 mV, measured by zeta potential measurements. Ibuprofen (IBU), a poorly water-soluble drug, was chosen as the model drug and encapsulated into the core of the NPs via a nano-precipitation method. The drug loading content (DLC) of the NPs prepared from mPEG-b-(PCL-g-PMAA) reached about 13%, with a drug loading efficiency (DLE) of above 75%. The in vitro release behavior of IBU from the NPs was pH-dependent. Typically, at pH 3.0 (0.01 M), the cumulative release percentage of IBU was about 40% over 12 h, whereas at pH 7.4 (0.01 M), more than 95% was released within 12 h for NPs prepared from mPEG₁₁₃-b-(PCL₉₁-g-PMAA₁₅₅). The MTT assay indicated that blank NPs prepared from mPEG-b-(PCL-g-PMAA) did not show significant toxicity against NCL-H460 cells. These results indicated that this new type of pH-dependent polymeric NPs prepared from mPEG-b-(PCL-g-PMAA) has great potential to be used as a drug carrier for the oral administration of hydrophobic drugs.