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Schematic diagram of the self-delivery of Janus nano-prodrug CPT-SS-GEM nanoparticles.A carrier-free and reduction-degradable Janus prodrug, termed as CPT-SS-GEM, was fabricated by redox-sensitive disulfide bond linked gemcitabine and camptothecin. This amphiphilic prodrug showed high drug loading capacity, 42.6% of CPT and 32.2% of GEM, respectively. Benefiting from its amphiphilic property, CPT-SS-GEM prodrug could self-assemble into Janus nano-prodrug in water without aid of any excipient. The morphology of the nano-prodrug was spherical particle confirmed by TEM. The rapid drug release from the nano-prodrug proceeded in a reduction-dependent manner, more than 90% of the native CPT and GEM were released in the mimic microenvironment of tumor cells (pH 6.5 PBS containing 2 mM DTT) within a period of 3 h. The concurrent and ratio-metric release of CPT and GEM endowed the Janus nano-prodrug CPT-SS-GEM with pronounced in vitro synergistic antiproliferative effect in multiple cancer cell lines when the inhibition rate of cancer cell proliferation exceeded 50%, including A549, NCI-H460, HCT116, HT-29, and MCF-7/ADR. The combination index values showed as followings, 1.04–0.4 (A549), 0.24–0.60 (NCI-H460), 0.42–0.16 (HCT116), 1.98–0.15 (HT-29), 0.36–0.19 (MCF-7/ADR). Taken together, the carrier-free, redox-sensitive Janus nano-prodrug CPT-SS-GEM is a promising candidate as synergistic combination of chemotherapeutics.