2. Academic Validation
  3. Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies

Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies

  • Nat Commun. 2024 Jun 12;15(1):5035. doi: 10.1038/s41467-024-49482-9.
Xijiao Ren # 1,  Rui Xue # 2,  Yan Luo # 3,  Shuang Wang 2,  Xinyue Ge 2,  Xuemei Yao 2,  Liqi Li 4,  Junxia Min 5,  Menghuan Li 6,  Zhong Luo 7 8,  Fudi Wang 9 10
Affiliations

Affiliations

  • 1 Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing, 400044, PR China.
  • 2 School of Life Science, Chongqing University, Chongqing, 400044, PR China.
  • 3 Radiation Oncology Center, Chongqing University Cancer Hospital, Chongqing, 400030, PR China.
  • 4 Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, PR China.
  • 5 The Second Affiliated Hospital, The First Affiliated Hospital School of Public Health Institute of Translational Medicine State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
  • 6 School of Life Science, Chongqing University, Chongqing, 400044, PR China. menghuanli@cqu.edu.cn.
  • 7 Key Laboratory of Biorheological Science and Technology, Ministry of Education, Chongqing University, Chongqing, 400044, PR China. luozhong918@cqu.edu.cn.
  • 8 School of Life Science, Chongqing University, Chongqing, 400044, PR China. luozhong918@cqu.edu.cn.
  • 9 The Second Affiliated Hospital, The First Affiliated Hospital School of Public Health Institute of Translational Medicine State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, 310058, PR China. fwang@zju.edu.cn.
  • 10 The First Affiliated Hospital Basic Medical Sciences, School of Public Health Hengyang Medical School University of South China, Hengyang, 421001, PR China. fwang@zju.edu.cn.
  • # Contributed equally.
PMID: 38866788 DOI: 10.1038/s41467-024-49482-9
Abstract

Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors. Specifically, fusogenic liposomes are loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 Aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplifies IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as adenosine triphosphate (ATP) for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulates matrix metalloproteinase-2 (MMP-2) expression that combined with released ATP to activate ACP through an "and" logic operation-like process (AND-gate), thus triggering the in-situ release of engineered cytosine-phosphate-guanine aptamer-based immunoadjuvants (eCpG) for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibits tumor-intrinsic vascular endothelial growth factor signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.

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