Photocatalysis/enzymolysis-based biomimetic Schottky junction reduces tumor interstitial solid and fluid phases for deep-penetrating tumor therapy

•The bio-Schottky junction can reduce both tumor interstitial solid and fluid phases.•The tumor interstitial hydrostatic pressure is reduced by 69.7%.•The drug penetration of Cu2O/Ag-P@M treated mice is 5.03-fold than the control group. Tumor interstitial solid phase-induced physical obstacles and fluid phase-induced hydrostatic pressure are regarded as the two main intractable barriers of drug delivery, leading to the survive of deep-seated tumor stem cells. Herein, a rational strategy is presented based on near-infrared light-stimuli enzymolysis and photocatalysis to decompose the tumor interstitial solid and fluid phases for boosting the tumor penetration of nanomedicine. In detail, a cuprous oxide/sliver nano-photocatalyst (Cu2O/Ag) is designed, which is covered with the thermosensitive papain-loaded tumor-homing homologous cytomembrane to form the nanomedicine (Cu2O/Ag-P@M). With the light irradiation, the heat generated by Cu2O/Ag promote the enzymolysis of extracellular matrix by papain, which eliminate the physical obstacles. Moreover, the photocatalytic water splitting of Cu2O/Ag reduce the volume of tumor interstitial fluid, which decrease the elevated hydrostatic pressure to boost the tumor penetration of nanomedicine. Additionally, during the intratumoral delivery, Cu2O/Ag-P@M is able to realize anti-tumor photothermal therapy and chemotherapy. The results indicate that the Cu2O/Ag-P@M decompose a majority of tumor extracellular matrix and interstitial fluid under light irradiation. The tumor interstitial hydrostatic pressure is reduced by 69.7%. The tumor penetration of Cu2O/Ag-P@M + L treated group is 5.03-fold than the Cu2O/Ag@M−L group, leading to the 95.19% of tumor inhibition rate.