Synthesis and characterization of starch based pH-responsive nanoparticles for controlled drug delivery are described. Polymethacrylic acid grafted starch (PMAA-g-St) nanoparticles with various molar ratio of starch to MAA were synthesized by a new one-pot method that enabled simultaneous grafting of PMAA and nanoparticle formation in an aqueous medium. NMR data showed that polysorbate 80 was polymerized into the graft polymer. Nanoparticles were relatively spherical with narrow size distribution and porous surface morphology and exhibited pH-dependent swelling in physiological pH range. The particle size and magnitude of volume phase transition were dependent on PMAA content and formulation parameters such as surfactant levels, cross-linker amount, and total monomer concentration. The results showed that the new pH-responsive nanoparticles possessed useful properties for controlled drug delivery.