A dual-warhead high-density lipoprotein mimetic nanomedicine simultaneously regulates stromal extracellular matrix and cGAS/STING activation for potent immunotherapy of cancer

Abstract

Immunotherapy has shown great potential for cancer treatment in the clinic. However, the inherent physical barrier of abundant extracellular matrix (ECM) and the biological barrier of immunosuppressive microenvironment have greatly hindered the intratumoral infiltration of effector T cells. Herein, a dual-warhead high-density lipoprotein (HDL) mimetic nanomedicine is constructed that can regulate stromal ECM and cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) activation for potent immunotherapy of cancer. After coating the HDL-mimetic outer layer and encapsulation of the transforming growth factor beta (TGF-β) receptor inhibitor LY3200882 (LY) on the hollow manganese dioxide nanoparticles loaded with glucose oxidase, the nanomedicine can target the tumor tissue with high efficiency. In the weak acidic tumor microenvironment, LY is released from the nanomedicine and destroys the physical barrier of ECM by inhibition the TGF-β receptor. After being endocytosed by tumor cells, the manganese ion is released and promotes the self-enhanced chemodynamic therapy. The damage-associated molecular patterns release and the cGAS/STING signaling pathway activation together destroy the biological barrier of immunosuppressive microenvironment. This nanomedicine thus shows potent antitumor efficiency on subcutaneous tumor model, tumor metastasis mice model and tumor recurrence mice model, providing a new strategy for amplifying the cancer immunotherapy.