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Published on: February 14, 2025
Artificially Modified NK Cell-Based Synergistic Immuno-Gene-Photodynamic Therapy for Cancer
Jiale Wu1,2, Kaihong Shi1,2, Wei Chao1,2
1Department of Pharmacy, Xuzhou Medical University, Xuzhou, People's Republic of China.
Background:
The immunotherapeutic approach utilizing Natural Killer (NK) cells for cancer treatment has garnered significant interest owing to its inherent cytotoxicity, immunomodulatory properties, demonstrated safety in in vivo studies. However, multiple immunosuppressive mechanisms in the tumor microenvironment (TME) suppress the anticancer effect of NK cells in the treatment of solid tumors. Herein, a smart NK cell drug delivery system (DDS) with photo-responsive and TME-responsive properties was designed.
Methods:
The NK cell DDS consists of two parts: the carrier is living NK cell with pH-low (abbreviated as NKpH) insertion peptide on its surface, the cargo is reductive-responsive nanogel (NG) encapsulated siRNA and photosensitizer (abbreviated as SP-NG), the final carrier was abbreviated as SP-NG@ NKpH. Firstly, pHLip helped artificially modified NK cell target and anchor onto cancer and exert the efficacy of cellular immunotherapy. Then, the strategy of combining photoactivation and bioreduction responsiveness achieved the precise release of cargos in cancer cells. Finally, the DDS combined the effect of the immunotherapy of NK cell, the gene therapy of siRNA, and the photodynamic therapy of photosensitizer.
Results:
Under near-infrared laser irradiation, SP-NG@NKpH induced an increase in reactive oxygen species (ROS) within cells, exacerbated cell membrane permeability, and allowed for rapid drug release. Within the tumor microenvironment (TME), NG exhibits highly sensitive reducibility for drug release. The SP-NG released from NK cells can be uptaken by tumor cells. When exposed to near-infrared laser irradiation, SP-NG@NKpH demonstrates significant tumor-targeting specificity and cytotoxicity.
Discussion:
The combined effect of the immunotherapy of NK cell, the gene therapy of siRNA, and the photodynamic therapy of photosensitizer obtained a stronger cancer killing effect in vitro and in vivo. Therefore, this versatile NK cell DDS exhibits a good clinical application prospect.
Insights
This study introduces a smart Natural Killer (NK) cell drug delivery system (DDS) that combines immunotherapy, gene therapy, and photodynamic therapy for enhanced cancer treatment. The novel DDS shows significant potential for solid tumor therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Natural Killer (NK) cells offer potent anti-cancer properties but are hindered by the tumor microenvironment (TME).
- Existing immunotherapies face challenges in solid tumors due to immunosuppressive TME mechanisms.
- A novel drug delivery system (DDS) is needed to overcome TME-mediated suppression of NK cell therapy.
Purpose of the Study:
- To design and evaluate a smart NK cell DDS with photo-responsive and TME-responsive properties.
- To enhance the efficacy of NK cell-based cancer immunotherapy.
- To combine NK cell immunotherapy, siRNA gene therapy, and photodynamic therapy for synergistic anti-cancer effects.
Main Methods:
- Developed a DDS (SP-NG@NKpH) using NK cells modified with pH-low insertion peptide (pHLIP) as carriers.
- Encapsulated siRNA and a photosensitizer within a reductive-responsive nanogel (NG) as cargo.
- Utilized photoactivation and bioreduction responsiveness for precise cargo release within cancer cells.
Main Results:
- The SP-NG@NKpH system demonstrated targeted delivery and anchoring to cancer cells via pHLip.
- Near-infrared laser irradiation triggered ROS generation and rapid drug release.
- The DDS exhibited significant tumor-targeting specificity and enhanced cytotoxicity in vitro and in vivo.
Conclusions:
- The combined therapeutic approach of NK cell immunotherapy, siRNA gene therapy, and photodynamic therapy yielded a potent anti-cancer effect.
- This versatile NK cell DDS shows promising clinical application prospects for solid tumor treatment.
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