International Journal of Nanomedicine (Nov 2024)

Artificially Modified NK Cell-Based Synergistic Immuno-Gene-Photodynamic Therapy for Cancer

  • Wu J,
  • Shi K,
  • Chao W,
  • Qin Z,
  • Hu Y,
  • Yang Y,
  • He Y,
  • Hua Y,
  • Zhao Z

Journal volume & issue
Vol. Volume 19
pp. 12323 – 12342

Abstract

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Jiale Wu,1,2 Kaihong Shi,1,2 Wei Chao,1,2 Zeyu Qin,1,2 Youhui Hu,1,2 Yihua Yang,1,2 Yuan He,1,2 Yabing Hua,1,2 Ziming Zhao1,2 1Department of Pharmacy, Xuzhou Medical University, Xuzhou, People’s Republic of China; 2Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People’s Republic of ChinaCorrespondence: Yabing Hua; Ziming Zhao, Department of Pharmacy, Xuzhou Medical University, Xuzhou, PR China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, People’s Republic of China, Email [email protected]; [email protected]: 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. Keywords: natural killer cells, photo-responsive, TME-responsive, anticancer, cellular immunotherapy, nanogel

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