Overcoming the tumor biological barrier: a multistage drug delivery strategy for DDR1-mediated resistant colorectal cancer therapy

Abstract Chemotherapy resistance remains a significant challenge in the treatment of colorectal cancer (CRC). The roles of discoidin domain receptor 1 (DDR1) in mediating tumor-collagen interactions and promoting cancer progression have been extensively studied. However, the specific mechanisms of DDR1 contribute to matrix-mediated drug resistance (MMDR) remain poorly understood. In this study, we elucidated a novel mechanism in which the interactions between tumor cells and collagen lead to promotion of drug efflux and collagen fiber alignment as well as suppression of immune infiltration, resulting in MMDR in CRC. To address this issue, we employed a multistage drug delivery system carrying Ddr1-siRNA and chemotherapeutic agents to disrupt collagen deposition and alignment by silencing DDR1 in ECM, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.