Abstract

As it is closely associated with tumor proliferation, metastasis, and the immunosuppressive microenvironment, the dysfunctional Hippo pathway has become an extremely attractive target for treating multiple cancers. However, to date, the corresponding chemotherapeutic nanomedicines have not been developed. Herein, a supramolecular self-delivery nanomedicine with in situ transforming capacity was tailor-constructed for Hippo-pathway restoration, and its inhibitory effect against tumor growth and metastasis was investigated in a highly aggressive triple-negative breast cancer (TNBC) model. Stimulated by overexpressed glutathione (GSH) and esterase in cancer cells, the self-assembled nanomedicine transformed from inactive nanospheres to active nanofibers conjugating tyrosvaline and spatiotemporally synchronously released the covalently linked flufenamic acid in situ, together activating the maladjusted Hippo pathway by simultaneously acting on different targets upstream and downstream. The transcriptional expression of Yes-associated protein (YAP) and related growth-promoted genes were significantly reduced, finally significantly repressing the proliferation and metastasis of cancer cells. Additionally, the Hippo-pathway restoration showed an excellent radiosensitization effect, making the targeted therapy combined with radiotherapy display a prominent synergistic in vivo anticancer effect against TNBC. This work reports a specifically designed smart nanomedicine to restore the function of the Hippo pathway and sensitize radiotherapy, providing an attractive paradigm for targeted drug delivery and cancer combination therapy.