Metformin-Mediated Immunosuppressive Microenvironment Remodeling in Combination with Chemotherapy via a Spatial-Specific Multi-Responsive Carrier-Free Self-Assembled Nanoparticle

The complex tumor immune pathology requires a precise spatial-control release of the combination drugs, but most multi-drug loaded nanoparticles release all drugs simultaneously in the tumor microenvironment (TME), making them difficult to reach the exact action site. To address the spatial specific release of drugs, a carrier-free self-assembled multi-responsive nanodrug delivery system is designed, in which p-phthalaldehyde (p-APA) and dithiodipropionic acid are used to connect metformin (MET) and 7-ethyl-10-hydroxycamptothecin (SN38) through a matrix metalloproteinase-2 (MMP-2) responsive peptide, and dipyridamole (DIP) is further loaded (MA-GPLGVRGDK-SS-SN38@DIP, MR NPs). The MR NPs first target tumor by enhanced permeability and retention effect, then the highly expressed MMP-2 at tumor site cleaves GPLGVRGDK, breaking the nanoparticle into three parts-DIP, MA-GPLG, and VRGDK-SS-SN38. DIP automatically binds with platelets in TME, inhibiting their function and restraining tumor metastasis. MA-GPLG releases MET in response to the acidic TME to reverse the immunosuppressive networks through PD-L1 downregulation and M2-like macrophages repolarization. Moreover, VRGDK-SS-SN38 binds to the overexpressed integrin alpha v beta 3 receptor to achieve tumor cells specific delivery and precise killing. Overall, this study offers an intelligent spatial-specific multi-responsive carrier-free drug delivery system in breast cancer, which releases drug spatial specifically, therefore reverses the tumor immunosuppressive microenvironment and inhibits metastasis. A novel spatial-specific multi-responsive carrier-free self-assembled drug delivery system (MA-GPLGVRGDK-SS-SN38@DIP, MR NPs) which conjugates metformin and SN38 through an MMP-2 responsive peptide and encapsulates dipyridamole is constructed. This multi-responsive system achieves a precise spatial-control release of the combination drugs, therefore, reverses the tumor immunosuppressive microenvironment and inhibits metastasis in breast cancer. image