Self-Assembled Aza-Boron-Dipyrromethene for Ferroptosis-Boosted Sonodynamic Therapy.

The presence of apoptosis inhibition proteins renders the cancer cells resistant to apoptosis, severely compromising the antitumor efficacy of sonodynamic therapy (SDT). Here, an intelligent anticancer nanoplatform based on an Aza-boron-dipyrromethene dye (denoted as Aza-BDY) is elaborately established for ferroptosis augmented SDT through cysteine (Cys) starvation. After endocytosis by tumor cells, Aza-BDY serves as both a ferroptosis inducing agent and a sonosensitizer for tumor treatment. The specific Cys response facilitates the disruption of redox homeostasis and initiation of cellular ferroptosis. Meanwhile, the released sonosensitizer causes efficient SDT and augments ferroptosis under ultrasound irradiation. Detailed in vitro and in vivo investigations demonstrate that the synergistic effect of Cys depletion and singlet oxygen (1 O2 ) generation significantly induces cancer-cell death and suppresses tumor proliferation with a high inhibition rate of 97.5 %.

Chemotherapy-enabled/augmented cascade catalytic tumor-oxidative nanotherapy.

Catalytic cascade transformations, which occur in spatially constrained tumor environment to generate therapeutic moieties from prodrugs or intrinsic species, are highly desirable for precise cancer therapy. Nevertheless, it is high challenging to engineer a cascade nanoreactor with tumor microenvironment (TME)-responsive capability for synergistic tumor therapy. Inspired by the biocatalytic cascades in biological processes, here, a tumor-specific nanoreactor was established to activate cascade reactions for oxidative stress-augmented chemotherapy by the integration of an artificial enzyme, Pt(IV)-based prodrug (Pt(IV)), with Cu(II)-based metal-organic frameworks (CuMOF). Upon internalization of CuMOF@Pt(IV) by tumor cells, in addition to chemotherapeutic effect, the activated cisplatin by glutathione (GSH) reduction is capable of acting as an artificial enzyme to elevate the hydrogen peroxide (H2O2) level through cascade reactions for augmenting the therapeutic efficacy of Cu+-mediated chemodynamic therapy (CDT). Meanwhile, CuMOF@Pt(IV) specifically deplete overexpressed GSH at tumor sites, thus amplifying tumor oxidative stress, and finally leading to augmented antitumor efficacy. The orchestrated cooperative effect of chemotherapy and oxidative stress presents splendid therapeutic efficacy on tumor-bearing mice with negligible adverse effects. Therefore, this cascade nanoreactor provides exciting opportunities to develop complementary therapeutic modalities for precise cancer treatment.