2. Academic Validation
  3. Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer

  • J Nanobiotechnology. 2024 Jun 19;22(1):348. doi: 10.1186/s12951-024-02612-3.
Shang Chen 1 2,  Yan He 1 3,  Xin Huang 1 4,  Yao Shen 1,  Qingshuang Zou 5,  Gun Yang 1 3,  Li Fu 6,  Quan Liu 7,  Dixian Luo 8
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen University, Shenzhen, 518052, People's Republic of China.
  • 2 Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen, 518060, People's Republic of China.
  • 3 Institute of Pharmacy and Pharmacology, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
  • 4 Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, People's Republic of China.
  • 5 Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, People's Republic of China.
  • 6 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518055, People's Republic of China. gracelfu@szu.edu.cn.
  • 7 Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen University, Shenzhen, 518052, People's Republic of China. liu_quan2020@163.com.
  • 8 Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital), Shenzhen University, Shenzhen, 518052, People's Republic of China. luodixian_2@163.com.
PMID: 38898486 DOI: 10.1186/s12951-024-02612-3
Abstract

Tumor-associated macrophages (TAMs) are a promising target for Cancer Immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD Peptides targeting Integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and Cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted Cancer Immunotherapy with potential for clinical application.

Keywords

Dual-targeting; Liver cancer; Small interfering RNA; Tumor-associated macrophage; m6A reader YTHDF1.

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