The combination of different therapies into a single platform has attracted increasing attention as a potential synergistic tumor treatment. Herein, the fabrication of a novel folate targeted system for chemo-photothermal therapy by using thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs) as a drug-loading vehicle is described. The novel targeted molecular bovine serum albumin-folic acid-modified MoS2 sheets (MoS2PEI- BSA-FA) were successfully synthesized and characterized, and then utilized as a capping agent to block PMOs to control the drug release and to investigate their potential in near-infrared photothermal therapy. The resulting PMOs-DOX@ MoS2-PEI-BSA-FA complexes had a uniform diameter (196 nm); high DOX loading capacity (185 mg.g PMOs-SH); excellent photothermal transformation ability; and good biocompatibility in physiological conditions. The PMOs-DOX@ MoS2-PEI-BSA-FA exhibited pH-dependence and near infrared (NIR) laser irradiation-triggered DOX release. In vitro experimental results confirmed that the material exhibits excellent photothermal transfer ability, outstanding tumor killing efficiency and specificity to target tumor cells via an FA-receptor-mediated endocytosis process. The in vivo experiments further demonstrated that the platform for synergistic chemo-photothermal therapy could significantly inhibit tumor growth, which is superior to any monotherapy. Meanwhile, cytotoxicity assays and histological assessments show that the engineered PMOs@ MoS2-PEI-BSA-FA have good biocompatibility, further inspiring potential biomedical applications. Overall, this work describes an excellent drug delivery system for chemo-photothermal synergistic targeted therapy having good drug release properties, which have great potential in cancer therapy.