An erythrocyte membrane-camouflaged fluorescent covalent organic framework for starving/nitric oxide/immunotherapy of triple-negative breast cancer

It is a great challenge to effectively treat triple-negative breast cancer (TNBC) due to lack of therapeutic targets and drug resistance of systemic chemotherapy. Rational design of nanomedicine with good hemocompatibility is urgently desirable for combination therapy of TNBC. Herein, an erythrocyte membrane-camouflaged fluorescent covalent organic framework (COF) loaded with an NO donor (hydroxyurea, Hu), glucose oxidase (GOx) and cytosine–phosphate–guanine oligonucleotides (CPG) (COF@HGC) was developed for imaging-guided starving/nitric oxide (NO)/immunization synergistic treatment of TNBC. The substances of HGC are easily co-loaded onto the COF due to the ordered pore structure and large surface area. And a folic acid-modified erythrocyte membrane (FEM) is coated on the surface of COF@HGC to improve targeted therapy and haemocompatibility. When COF@HGC@FEM is internalized into tumor cells, hemoglobin (Hb) on FEM and GOx loaded on the COF can trigger cascade reactions to kill tumor cells due to the simultaneous production of NO and exhaustion of glucose. Meanwhile, the COF with excellent fluorescence properties can be used as a self-reporter for bioimaging. Furthermore, the CPG can reprogram tumor-associated macrophages from tumor-supportive phenotype to anti-tumor phenotype and enhance immunotherapy. Through the “three-in-one” strategy, the biomimetic nanoplatform can effectively inhibit tumor growth and reprogram the tumor immunosuppression microenvironment in the TNBC mouse model.