A biocompatible, caspase-3-responsive, and fluorescence-quenching smart apoptosis nanprobe based on a PEGlyated nanogel that contains gold nanoparticles (GNRs) (fluorescence quenchers) in the cross-linked polyamine gel core and fluorescein isothiocyanate (FITC)-labeled DEVD peptides at the tethered PEG chain ends is prepared for monitoring the cancer response to therapy. FITC-DEVD-nangel-GNP shows very little fluorescence in the absence of activated caspase-3 (normal cells) through the fluoresence resonance energy transfer (FRET), process between the GNPs and the FITC molecules, while pronounced fluorescence signals are observed in apoptotic cells because of the clevage of the DEVD peptide by activated caspase-3 present in the cells, which results in the release of FITC molecules. Thus, remarkable quenching and dequenching of fluoresence signals in response to activated caspase-3 is observed. Apoptotic cells are detected in human hepatocyte (HuH-7) multicellular tumor spheroids (MCTSs), a commonly used three dimensional m vitro model mimicking the in vivo biology of tumors, as early as one day post-treatment with staurosporine, an apoptosis-inducing agent; while growth-inhibition (i.e., change in size) of the HuH-7 MCTs is only observed after a delay of three days (i.e., on day 4). This demonstrates the effectiveness of the FITC-DEVD-nanogel-GNP probe as a smart nanoprobe for real-time monitor as well as more rapid assessment of the early response to cancer therapy.