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The use of targeted drug delivery systems to accumulate medications in cancer cells, along with the simultaneous application of multiple drugs, can facilitate the administration of optimal doses, leading to more efficient treatment as well as reduced side effects. We fabricated zirconium-based UiO-66-NH₂ metal-organic framework (MOF) nanoparticles (NPs) with folic acid (FA) conjugated onto their surface for targeted delivery of doxorubicin (DOX), and smart drug release within tumor cells. Following the physicochemical characterization of the prepared NPs, the drug release profile was investigated in simulated media with pH 5.4 and 7.4. Subsequently, the internalization and anticancer effects of the NPs were evaluated in HT-29 and HEK-293 cells to assess their selectivity. Simultaneous treatment of HT-29 cells with FA-decorated NPs and hydroxychloroquine (HCQ), an autophagy inhibitor, was performed to sensitize cancer cells. The synergistic effects of combined treatment were assessed through MTT assay and autophagy flux detection. UiO-66-NH₂-FA@DOX NPs with a surface area of 323 m²/g and a high loading capacity of 36.25% showed a pH-dependent release with a substantial increase in acidic condition. Higher uptake of targeted NPs in HT-29 cells led to higher cytotoxicity and apoptosis. The combination of HCQ and targeted NPs increased cytotoxic effects against HT-29 cells compared to treatment with targeted NPs alone. Acridine orange staining revealed different patterns of autophagy flux in the co-administered drug groups. This study suggests that our DOX-loaded targeted nanocarrier enhances the therapeutic efficacy through localized drug delivery and reduced potential side effects compared to conventional DOX treatment. Its combination with HCQ may offer a promising strategy for safer and more effective colorectal cancer therapy by enabling dose reduction of both agents. However, further in vivo studies are necessary to validate these findings.