Targeted nanoparticles with triggered lysosomal escape enable anti-angiogenic immunotherapy for peritoneal metastatic colorectal cancer

Peritoneal metastatic colorectal cancer (PMC) is highly aggressive and resistant to anti-angiogenic monotherapy due to the angiogenesis–immunosuppression vicious cycle. This study develops dual-ligand modified nanoparticles (Reg/DMX@BPF NPs), co-loaded with the angiogenesis inhibitor regorafenib (Reg) and the stimulator of interferon genes (STING) agonist DMXAA (DMX). Reg prevents DMX aggregation as a molecular scaffold via π – π stacking. The folic acid (FA) and phenylboronic acid (PBA)-functionalized BSA (BPF) facilitates active tumor targeting and metastatic site enrichment. Upon internalization into lysosomes, the acidic pH triggers boronate ester bond formation between PBA and glycoproteins, inducing lysosomal disruption and efficient cytosolic release. In addition to STING activation, the BPF potently activates toll-like receptor 4 signaling, synergistically inducing M1 tumor-associated macrophages polarization and dendritic cells maturation. In vivo results demonstrate that Reg/DMX@BPF NPs synergistically inhibit tumor proliferation, normalize pathological vasculature, and reprogram the immunosuppressive microenvironment, which leads to reduced tumor burden and ascites. Collectively, the targeted lysosome-escape nanoparticles provide a novel strategy to overcome the poor efficacy of anti-angiogenic therapy against PMC. Engineered Reg/DMX@BPF NPs enable tumor-targeted delivery, where PBA facilitates lysosomal escape, thereby synergistically disrupting the angiogenesis–immunosuppression vicious cycle in peritoneal metastatic colorectal cancer.