In Situ Transformable Supramolecular Nanomedicine Targeted Activating Hippo Pathway for Triple-Negative Breast Cancer Growth and Metastasis Inhibition

As it is closely associated with tumor proliferation, metastasis, and the immunosuppressive microenvironment, the dysfunc-tional Hippo pathway has become an extremely attractive target for treating multiple cancers. However, to date, the corresponding chemo-therapeutic nanomedicines have not been developed. Herein, a supra -molecular 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 synchro-nously 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.