Major challenges in the development of effective stimuli-responsive nanogels as targeted drug and gene delivery carriers are to improve biocompatibility, stability, and controlled release during systemic circulation. In this work, biofunctional nanogels based on copolymers of poly(N-2-hydroxyethyl acrylamide) (polyHEAA) and acrylic acid (AA) with controlled size and morphology are synthesized using an inverse-microemulsion free-radical polymerization method. The chemical composition, size, swelling behavior, physical stability, and antifouling ability of the poly(HEAA/AA) nanogels are characterized by FTIR, dynamic light scattering, and atomic force microscopy. The cell viability and uptake of the nanogels are evaluated under physiological conditions. The controlled release of drugs in the nanogels is measured in both aqueous media and cell culture upon changes in pH and salt concentration. The poly(HEAA/AA) nanogels exhibit both superlow fouling ability to resist nonspecific protein adsorption and ultrastability to keep their hydrodynamic sizes unchanged in 100% human blood plasma for 30 days in vitro. The controlled release of Rhodamine 6G encapsulated in poly(HEAA/AA) nanogels is demonstrated at a low pH and high salt concentration. More importantly, the conjugation of transferrin with poly(HEAA/AA) nanogels allows the uptake of nanogels by SH-SY5Y cells and triggering of intracellular drug release, while not inducing cytotoxicity to cells similar to innate cell viability. HEAA/AA-based nanogels hold great potential as drug delivery carriers in vivo, because they integrate ultrastability, superlow fouling ability, and environmental-responsive controlled release property into one chemical entity.