Assembly of FA/PBA-functionalized albumin nanoparticles with hyaluronic acid-mitomycin C for integrated chemo-antiangiogenic therapy and macrophage reprogramming in colorectal cancer peritoneal metastasis

Colorectal cancer peritoneal metastasis (PM) is characterized by rapid progression, pathological angiogenesis, malignant ascites, and an M2 macrophage-dominated tumor microenvironment, which limit the efficacy of single-agent therapy. Herein, we constructed Reg@BFP-HM NPs by associating a hyaluronic acid-mitomycin C (HA-MMC, HM) with regorafenib-loaded folic acid/phenylboronic acid-modified bovine serum albumin nanoparticles (Reg@BFP NPs). Reg@BFP and HM were assembled into an integrated nanostructure through multiple interactions. As a targeted therapeutic nanoplatform, BFP-HM enables folate receptor/CD44-mediated tumor delivery and improves the dispersion of Reg and MMC. After intraperitoneal administration, Reg@BFP-HM NPs showed stronger antitumor efficacy than either component alone. HM exerts potent cytotoxicity to eliminate tumor cells, whereas Reg inhibits angiogenesis and tumor proliferation through suppression of the VEGFR2/ERK pathway. In addition, BFP activates the TLR4/NF-κB pathway to promote macrophage reprogramming toward a pro-inflammatory phenotype, which acts in synergy with Reg to suppress the formation of malignant ascites. In a CT26-luc PM mouse model, Reg@BFP-HM NPs inhibited peritoneal tumor growth, markedly reduced ascites volume, and prolonged survival without obvious systemic toxicity. These results highlight the potential of Reg@BFP-HM NPs as a chemo-antiangiogenic strategy for PM treatment.