To improve the biocompatibility and biodegradability of nanocarriers, well-defined poly(vinylcaprolactam)-based acid degradable nanogels were fabricated for drug delivery via precipitation polymerization in water, where synthetic ketal-based 2,2-dimethacroyloxy-1-ethoxypropane (DMAEP) acted as cross-linker, and N-(2-hydroxypropyl)methacrylamide (HPMA) served as co-monomer. Expectedly, we observed that the environment temperature and pH play important roles in the performance of the nanogels. The nanogels were reduced in size upon increasing temperature and showed higher volume phase transition temperature (VPTT) with feeding higher concentration of HPMA. With the incorporation of ketal linkages, the nanogels showed accelerated degradation profiles by lowering the pH and increasing temperature of the incubation medium. When used as nanocarrier of anticancer drug Doxorubicin (DOX), compared to non-degradable nanogels with similar components, the acid-degradable nanogels displayed more effective drug controlled release behaviour, low drug leakage of DOX at neutral pH while rapid and sufficient release from the nanogels under acidic condition. The results of the cytotoxicity and hemolysis assays further highlighted that the acid-degradable nanogel showed no hemolysin but excellent viability to normal cells, and DOX-loaded nanogel presented higher proliferation inhibition against tumor cells.