Abstract

Peritoneal metastasis of colorectal cancer (PM-CRC) represents a major therapeutic challenge in advanced disease, where aberrant tumor vasculature contributes to poor prognosis. To address the pharmacological limitations of regorafenib (REG), this study developed a dual-receptor-targeted nanoplatform (REG@LFHA NPs) that leverages the characteristic overexpression of LRP-1 and CD44 receptors in the colorectal cancer tumor microenvironment. The nanoplatform was engineered through nanoprecipitation and electrostatic self-assembly, incorporating lactoferrin for LRP-1 targeting and hyaluronic acid for CD44 recognition. REG@LFHA NPs exert multifaceted antitumor effects through three coordinated mechanisms: potent suppression of tumor vasculature through VEGF-VEGFR pathway blockade, effectively disrupting blood and oxygen supply to induce tumor necrosis; direct tumor cytotoxicity via REG-mediated apoptosis and cell cycle arrest; and immune microenvironment remodeling through macrophage repolarization from pro-tumor M2 to antitumor M1 phenotypes. In PM-CRC models, REG@LFHA NPs demonstrated significantly enhanced tumor accumulation and therapeutic efficacy compared to free REG. Furthermore, the nanoplatform showed remarkable synergy with oxaliplatin, the first-line chemotherapeutic agent for PM-CRC, producing superior treatment outcomes through complementary mechanisms of action. This study not only establishes REG@LFHA NPs as an effective dual-targeting nanomedicine but also demonstrates their strong potential for clinical translation, particularly in combination with standard chemotherapy regimens for advanced peritoneal metastatic colorectal cancer.