Abstract

The tumor microenvironment (TME) is composed of tumor cells, blood vessels, cancer-associated fibroblasts (CAFs), tumor extracellular matrix (ECM), et al. The TME is closely related to anticancer treatment outcome. In this manuscript, a multifunctional nanomedicine (denoted as ZDCMH NP), combining multiple TME destruction strategies into one delivery system, has been designed and fabricated. In brief, zinc phthalocyanine (ZnPc, a photosensitizer), bromopentacarbonylmanganese(I) (COMn, a CO donor), and losartan (Dup, a CAF inhibitor) were coloaded inside mesoporous silica nanoparticles (MSNs). After that, a cross-linked hyaluronic acid (HA) gel shell was encapsulated onto the surface of the MSNs to form ZDCMH NPs. After arriving at the tumor tissue, the HA gel shell could be degraded by hyaluronidase (HAase) in the ECM to trigger encapsulated drug release. After light irradiation, ZnPc generated abundant reactive oxygen species (ROS), which could provide photodynamic therapy (PDT) activity and induce COMn to release CO, which could improve the enhanced permeability and retention (EPR) effect to promote ZDCMH NP accumulation in tumor tissue. The released Dup could inhibit CAF activity and downregulate the collagen fiber concentration in the TME to promote the deep penetration of ZDCMH NPs inside solid tumors. In vitro and in vivo anticancer studies have indicated that the destruction of the TME by multiple strategies is very helpful for ZnPc to obtain satisfactory PDT efficiency.