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Targeted nanoparticles with triggered lysosomal escape enable anti-angiogenic immunotherapy for peritoneal metastatic
Meng Wang1, Yutong Qian1, Yicong Li1
1Institute of Biomaterials and Nanomedicine, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
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.
Insights
New nanoparticles co-loaded with regorafenib and DMXAA overcome resistance in peritoneal metastatic colorectal cancer. This targeted therapy combination inhibits tumor growth and reduces ascites by reprogramming the tumor microenvironment.
Area of Science:
- Oncology
- Nanomedicine
- Immunology
Background:
- Peritoneal metastatic colorectal cancer (PMC) exhibits high aggressiveness and resistance to anti-angiogenic monotherapy.
- A critical factor is the angiogenesis-immunosuppression vicious cycle within the tumor microenvironment.
Purpose of the Study:
- To develop dual-ligand modified nanoparticles (Reg/DMX@BPF NPs) for targeted delivery of regorafenib (Reg) and DMXAA (DMX).
- To overcome resistance in PMC by simultaneously inhibiting angiogenesis and stimulating the immune response.
Main Methods:
- Nanoparticles co-loaded with regorafenib and DMXAA, functionalized with folic acid (FA) and phenylboronic acid (PBA) on BSA (BPF) for active targeting.
- Utilized π-π stacking for Reg preventing DMX aggregation and boronate ester bonds for lysosomal escape and cytosolic release.
- Investigated STING and Toll-like receptor 4 (TLR4) pathway activation in immune cells.
Main Results:
- Reg/DMX@BPF NPs demonstrated effective tumor targeting and enrichment at metastatic sites.
- Successful lysosomal disruption and cytosolic release of payloads, leading to STING and TLR4 activation.
- Synergistic inhibition of tumor proliferation, normalization of tumor vasculature, and reprogramming of the immunosuppressive microenvironment (M1 macrophage polarization, dendritic cell maturation).
- Significant reduction in tumor burden and ascites in vivo.
Conclusions:
- Targeted lysosome-escape nanoparticles offer a novel strategy to combat PMC.
- The dual-ligand NPs effectively overcome the limitations of anti-angiogenic monotherapy by modulating both tumor and immune components.
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