LRP-1/CD44-targeted regorafenib nano-delivery system leveraging anti-angiogenesis and synergistic cytotoxicity against peritoneal metastasis of colorectal cancer

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. Schematic illustration of REG@LFHA NPs design and their synergistic therapeutic mechanism against PM-CRC: (I) Combines with OxP to kill tumor cells; (II) Targets and prunes pathological vasculature through blockade of the VEGF-VEGFR pathway; (III) Reprograms M2 macrophages toward tumoricidal M1 phenotypes to reverse immunosuppression. • LF/HA functionalization enables tumor-selective LRP-1/CD44 dual-targeting. • The LRP-1/CD44 dual-targeting delivery system enables deep penetration in 3D tumor spheroid models. • REG@LFHA NPs prunes the aberrant tumor vasculature to suppress metastasis and oxygen delivery. • REG and LF synergistically induce M2-to-M1 phenotypic reprogramming of macrophages to reverse immunosuppression. • REG@LFHA NPs and OxP potently suppress PM-CRC progression.