A novel class of pH-responsive hollow poly(L-glutamic acid)/chitosan (PLGA/CS) nanogels was fabricated by a templating approach, which was mild and surfactant free, and combined with a “grafting from” method and intermacromolecular crosslinking technique. The surface grafting, crosslinking reaction, nanogel fabrication and microstructure were investigated by FTIR, ¹H NMR, XRD, TGA, light scattering, and electron microscopy. The size of the resultant PLGA/CS nanogels could be accurately controlled by simply changing the size of the silica template. The nanogels responded to changes in environmental pH, elucidated according to the variation of the size of the nanogels and zeta potential at different pH values. Taking water-soluble antineoplastic agent mitoxantrone (MTX) as a model drug, the nanogels presented high loading ability at high-pH environment and rapid MTX release behavior under acidic conditions. MTT assays used to study the in vitro cytotoxicity of PLGA/CS nanogels showed a negligible cytotoxicity in mouse fibroblast L929 cells. Compared with bare MTX, MTX loaded PLGA/CS nanogels exhibited an enhanced inhibition effect to human gastric carcinoma SGC7901 cells. Fluorescence microscopy and flow cytometry analysis results demonstrated efficient cellular uptake of the PLGA/CS nanogels into the cells. These studies suggest that such pH-responsive PLGA/CS hollow nanogels might have great potential in controlled drug delivery systems.