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Monocyte/Macrophage-Mediated Transport of Dual-Drug ZIF Nanoplatforms Synergized with Programmed Cell Death Protein-1
Xietao Ye1,2, Yuping Liu1,2,3, Liangyin Wei1,2
1Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.
Abstract:
Microsatellite-stable colorectal cancer (MSS-CRC) exhibits resistance to programmed cell death protein-1 (PD-1) therapy. Improving the infiltration and tumor recognition of cytotoxic T-lymphocytes (CTLs) is a promising strategy, but it encounters huge challenges from drug delivery and mechanisms aspects. Here, a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes derived from MSS-CRC cells is engineered for the co-delivery of ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC, named as Ab@Rg1/Att-ZIF. This system is selectively engulfed by Ly-6C+ monocytes during blood circulation and utilizes a "hitchhiking" mechanism to migrate toward the core of MSS-CRC. Ab@Rg1/Att-ZIF undergoes rapid disassembly in the tumor, released Rg1 promotes the processing and transportation of tumor antigens in dendritic cells (DCs), enhancing their maturation. Meanwhile, Att enhances the activity of the 26S proteasome complex in tumor cells, leading to increased expression of major histocompatibility complex class-I (MHC-I). These coordinated actions enhance the infiltration and recognition of CTLs in the center of MSS-CRC, significantly improving the tumor inhibition of PD-1 treatment from ≈5% to ≈69%. This innovative design, involving inflammation-guided precise drug co-delivery and a rational combination, achieves synergistic engineering of the tumor microenvironment, providing a novel strategy for successful PD-1 treatment of MSS-CRC.
Insights
This study developed a novel drug delivery system for microsatellite-stable colorectal cancer (MSS-CRC) that enhances cytotoxic T-lymphocyte (CTL) activity. The engineered nanoparticles significantly improved programmed cell death protein-1 (PD-1) therapy effectiveness against MSS-CRC.
Area of Science:
- Biomedical Engineering
- Cancer Therapy
- Drug Delivery Systems
Background:
- Microsatellite-stable colorectal cancer (MSS-CRC) is resistant to programmed cell death protein-1 (PD-1) immunotherapy.
- Enhancing cytotoxic T-lymphocyte (CTL) infiltration and tumor recognition is crucial for MSS-CRC treatment.
- Challenges exist in drug delivery and understanding mechanisms for effective MSS-CRC therapy.
Purpose of the Study:
- To engineer a novel drug delivery system for co-delivering ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) to MSS-CRC.
- To improve the efficacy of PD-1 therapy in MSS-CRC by enhancing CTL activity.
- To synergistically engineer the tumor microenvironment for improved cancer treatment.
Main Methods:
- Fabrication of a zeolitic imidazolate framework (ZIF) coated with apoptotic body membranes (Ab@Rg1/Att-ZIF) for co-delivery of Rg1 and Att.
- Utilizing a "hitchhiking" mechanism for targeted migration of the nanocarrier to MSS-CRC via Ly-6C+ monocytes.
- Investigating the effects of Rg1 on dendritic cell (DC) maturation and Att on MHC-I expression in tumor cells.
Main Results:
- The Ab@Rg1/Att-ZIF system effectively delivered Rg1 and Att to MSS-CRC.
- Rg1 promoted DC maturation and antigen presentation, while Att enhanced MHC-I expression.
- Coordinated actions significantly improved CTL infiltration and recognition, increasing PD-1 therapy efficacy from ≈5% to ≈69%.
Conclusions:
- The engineered Ab@Rg1/Att-ZIF system provides inflammation-guided, precise co-delivery of therapeutic agents.
- This strategy synergistically modifies the tumor microenvironment, enhancing anti-tumor immunity.
- This novel approach offers a promising strategy for overcoming PD-1 resistance in MSS-CRC.
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