Anionic Nanoparticles Co-Loaded with Regorafenib/Paclitaxel for Macrophage-Mediated Chemoimmunotherapy against Colorectal Peritoneal Metastases

The limited efficacy of intraperitoneal chemotherapy for colorectal peritoneal metastases (CPM) arises from its failure to remodel the tumor-promoting microenvironment dominated by M2-like macrophages. Here, we demonstrate that anionic nanoparticles coloaded with regorafenib (REG) and paclitaxel (PTX) are capable of overcoming this limitation by not only directly killing tumor cells but also reprogramming macrophages to the antitumor phenotype. We uncovered that anionic nanoparticles achieved superior retention and more balanced in vivo uptake by both tumor cells and macrophages compared with their cationic or neutral counterparts. Then, we fabricated anionic 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA) liposome-coated albumin-bound REG and PTX (DOPA@Alb-RP) and demonstrated that DOPA@Alb-RP treatment elicited potent and durable antitumor immunity and significantly prolonged survival in the mouse model of CPM. Impressively, the treatment achieved tumor eradication in 64% of the mice. This macrophage-engaging nanoplatform provides a rational approach to potentiating chemoimmunotherapy against peritoneal metastases.