BACKGROUND: Smart materials capable of responding to external stimuli are noteworthy candidates in designing drug delivery systems. In many of the recent research, temperature and pH have been recognized as the main stimulating factors in designing systems for anti-cancer drugs delivery systems. PURPOSE: In this study, thermo and pH-responsive character of a nano-carrier drug delivery platform based on lysine modified poly (vinylcaprolactam) hydrogel conjugated with doxorubicin was assessed. METHODS: Poly (vinylcaprolactam) cross-linked with poly (ethyleneglycol) diacrylate was prepared via RAFT polymerization, and the prepared structure was linked with lysine through ring-opening. The anti-cancer drug doxorubicin, was linked to lysine moiety of the prepared structure via Schiff-base reaction. The prepared platform was characterized by 1HNMR and FT-IR, while molecular weight characterization was performed by size exclusion chromatography. The temperature-responsive activity was evaluated using differential scanning calorimetry and dynamic light scattering. In vitro release pattern in simulated physiologic pH at 37°C was compared with acidic pH attributed to tumor site and elevated temperature. The anticancer efficiency of the drug-conjugated structure was evaluated in breast cancer cell line MCF-7 in 24 and 48 h, and cell uptake assay was performed on the same cell line. CONCLUSION: According to the results, well-structure defined smart pH and temperature responsive nano-hydrogel was prepared. The enhanced release rates are observed at acidic pH and elevated temperature. We have concluded that the doxorubicin-conjugated nanoparticle results in higher cellular uptakes and more cytotoxicity.