Light-enhanced Hypoxia-responsive Gene Editing for Hypoxia-resistant Photodynamic And Immunotherapy.

Hypoxia is a key hallmark of solid tumors and can cause resistance to various treatments such as photodynamic and immunotherapy. Microenvironment-responsive gene editing provides a powerful tool to overcome hypoxia resistance and remodel hypoxic microenvironments for enhanced tumor therapy. Here, we develop a light-enhanced hypoxia-responsive multifunctional nanocarrier to perform spatiotemporal specific dual gene editing for enhanced photodynamic and immunotherapy in breast cancer. As a gated molecule of nanocarrier, the degradation of azobenzene moieties under hypoxic conditions triggers controllable release of Cas9 ribonucleoprotein in hypoxic site of the tumor. Hyaluronic acid was conjugated with chloramine e6 to coat mesoporous silica nanoparticles for targeted delivery in tumor and generation of high levels of reactive oxygen species, which could result in increased hypoxia levels for effective cleavage of azobenzene bonds to improve gene editing efficiency and reduce toxic side effects with light irradiation. Moreover, dual targeting HIF-1α and PD-L1 in the anoxic microenvironments could overcome hypoxia resistance and remodel immune microenvironments, which reduced tumor plasticity and resistance to photodynamic and immunotherapy. In summary, we develop a light-enhanced hypoxia responsive nanocomposite for controllable gene editing which holds great promise for synergistic hypoxia-resistant photodynamic and immunotherapy. This article is protected by copyright. All rights reserved.