Matrix-degrading soft-nanoplatform with enhanced tissue penetration for amplifying photodynamic therapeutic efficacy of breast cancer†

The dense extracellular matrix (ECM) in the tumor microenvironment forms an abnormal physical barrier, which impedes the delivery and penetration of nanomedicines and hinders their therapeutic efficacy. Herein, we synthesize matrix-degrading soft-nanocapsules composed of human serum albumin (HSA) and hyaluronidase (HAase) for overcoming the obstruction of ECM in the tumor microenvironment. The matrix-degrading human serum albumin/hyaluronidase soft-nanocapsules, referred to as HSA/HAase SNCs, possess a uniform diameter, inward hollow structure, and wrinkled morphology. In vitro biocompatibility results indicate that the HSA/HAase SNCs display no adverse effects on the viability of human umbilical vein endothelial cells (HUVECs), smooth muscle cells (SMCs), and mouse breast cancer (4T1) cells and do not induce hemolysis towards red blood cells (RBCs). The HSA/HAase SNCs exhibit a 1.4-fold increase in tumor cellular uptake compared to the stiff-counterparts and enhanced penetration in 4T1-, mouse colon carcinoma 26- (CT26-), and mouse pancreatic cancer- (PanO₂-) multicellular spheroids. Thanks to the advanced biological properties, a photodynamic platform prepared by loading Ce6 in the HSA/HAase SNCs (HSA/HAase@Ce6) shows improved reactive oxygen species production, a stronger killing effect for cancer cells, and deeper penetration in tumor tissues. In vivo experiments show that HSA/HAase@Ce6 effectively inhibits tumor growth in breast cancer mouse models. RNA-seq analysis of the mice that received the treatment of HSA/HAase@Ce6 shows enrichment of signaling pathways associated with ECM-degradation, which demonstrates that the matrix-degrading nanocapsules overcome the ECM-induced physical barriers in tumors. Overall, the matrix-degrading soft-nanoplatform represents a highly promising strategy to overcome ECM-induced physical barriers and enhance the therapeutic efficacy of nanomedicines.