Development of unique theranostic nanoplatforms for tumor imaging and therapy remains an active topic in current nanomedicine. Here, we designed a novel targeted theranostic nanoplatform for enhanced -weighted magnetic resonance (MR) imaging-guided chemotherapy by constructing layered double hydroxide (LDH)-stabilized ultrasmall iron oxide (FeO) nanoparticles with hyaluronic acid (HA) modified as targeting agents, and anticancer drug doxorubicin (DOX) loaded with a high loading efficiency. : The structure and release property of LDH-FeO-HA/DOX nanoplatforms were characterized systematically. B16 melanoma cells with CD44 receptors overexpressed were used as model cells to determine the biocompatibility, targeting capability, and therapeutic efficiency of nanoplatforms. For experiment, hyaluronidase (HAase) pretreatment was combined with nanoplatform administration to investigate the MR imaging and chemotherapeutic effect. : The LDH-FeO-HA nanohybrids possess good colloidal stability and cytocompatibility, display an relaxivity 10-fold higher than the pristine ultrasmall FeO (4.38 mM s 0.42 mM s), and could release drug in a pH-responsive manner. experiments demonstrate that LDH-FeO-HA/DOX nanohybrids are able to specifically target B16 cells overexpressing CD44 receptors and effectively release DOX to nucleus. results show that with the pretreatment of tumor tissue by HAase to degrade the overexpressed HA in extra-cellular matrix, the designed nanoplatforms have a better tumor penetration for significantly enhanced MR imaging of tumors and tumor chemotherapy with low side effects. : The designed LDH-FeO-HA/DOX nanohybrids may be developed as a novel targeted theranostic nanoplatform for enhanced -weighted MR imaging-guided chemotherapy of CD44 receptor-overexpressing tumors.