Albumin Nanoparticle–Mediated Codelivery of Regorafenib and Paclitaxel Boosts Chemoimmunotherapy of Peritoneal Metastases

ABSTRACT Despite its well‐established clinical efficacy in multiple solid tumors, nab‐paclitaxel confers limited therapeutic benefit in metastatic colorectal cancer (mCRC), primarily attributed to intrinsic chemoresistance and macrophage‐mediated immunosuppression. Here, we find that regorafenib (REG) and paclitaxel (PTX) exhibit robust synergistic cytotoxicity against tumor cells, while also potentiating repolarization of macrophages from pro‑tumor M2 to antitumor M1 phenotype. To leverage this synergy and improve the therapeutic efficacy of albumin‐bound PTX in mCRC, we construct an albumin nanoparticle co‐loaded with REG and PTX (Alb‐RP). Alb‐RP facilitates macrophage phenotypic transition to the M1 state and upregulates proinflammatory cytokine expression, exhibiting potent tumoricidal activity in macrophage‐tumor cell co‐culture systems. In the MC38 colorectal peritoneal metastasis (CPM) model, Alb‐RP markedly suppresses tumor progression and prolongs survival, achieving complete tumor regression in 44% of treated mice. Meanwhile, Alb‐RP effectively reshapes the immune microenvironment in both peritoneal fluid and tumor tissues, characterized by decreased M2 macrophages, expanded M1 macrophages, enhanced dendritic cell activation, and increased infiltration of cytotoxic CD8 + T cells. Collectively, this study presents a translatable albumin‐based co‐delivery strategy that integrates direct chemotherapeutic cytotoxicity and macrophage repolarization to overcome the limited efficacy of albumin‐bound PTX against mCRC.