Stealth surface driven accumulation of Trojan Horse for tumor hypoxia relief in combination with targeted cancer therapy

The clearance of tumor-associated immune systems (TAISs) is the key impediment of the drug delivery, which leads to the low drug accumulation (0.7%) in the traditional chemotherapy. To tackle this issue, we constructed biomimetic nanoparticles serving as Trojan Horse, which consist of polydopamine (PDA) nanospheres with payloads of catalase (CAT), anticarcinogenic drug doxorubicin (Dox) and surrounding tumor cell membrane. Due to the coating of the homotypic cancer cell membrane, the Trojan Horse escaped the clearance of TAISs and heightened tumor-site target delivery. Sequentially, the over-expressive hydrogen peroxide in the tumor microenvironment penetrated the membrane of the Trojan Horse and reacted with CAT to generate oxygen, which realized the hypoxia relief. The hypoxia relief removed the immune resistance of tumors via the polarization of tumor-associated macrophages from M2 to M1 and broke the chemoresistance by downregulation of P-glycoprotein. With the oxygen generation, the cell membrane was broken and separated from the Dox-loaded PDA resulting in the immunotherapy by antigen presentation. Finally, the Dox-PDA nanospheres were taken into the tumor cells to achieve the chemo-phototherapy under near-infrared laser irradiation. The Trojan Horse showed higher accumulation (15.3%) over the enhanced permeability and retention effect (7.5%) of conventional nanodrugs and led to complete tumor eradication in vivo, which provides a promising treatment paradigm against tumor.