A pHe sensitive nanodrug for collaborative penetration and inhibition of metastatic tumors

Current chemotherapies for metastatic tumors are seriously restricted by limited drug infiltration and deficient disturbance of metastasis-associated complex pathways involving tumor cell autocrine as well as paracrine loops in the microenvironment (TME). Of note, cancer-associated fibroblasts (CAFs) play a predominant role in shaping TME favoring drug resistance and metastasis. Herein, we constructed a tumor extracellular pH (pH_e) sensitive methotrexate-chitosan conjugate (MTX-GC-DEAP) and co-assembled it with quercetin (QUE) to achieve co-delivered nanodrugs (MTX-GC-DEAP/QUE). The pH_e sensitive protonation and disassembly enabled MTX-GC-DEAP/QUE for stroma-specific delivery of QUE and positive-charged MTX-GC-DEAP molecular conjugates, thereby achieving deep tumor penetration via the combination of QUE-mediated CAF inactivation and adsorption-mediated transcytosis. On the basis of significantly promoted drug availability, a strengthened "omnidirectional" inhibition of pre-metastatic initiation was generated both in vitro and in vivo from the CAF inactivation-mediated reversion of metastasis-promoting environments as well as the inhibition of epithelial-mesenchymal transition, local and blood vessel invasion via QUE-mediated direct regulation on tumor cells. Our tailor-designed versatile nanodrug provides a deep insight into potentiating multi-faceted penetration of multi-mechanism-based regulating agents for intensive metastasis inhibition.