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

Xijiao Ren, Rui Xue, Yan Luo, Shuang Wang, Xinyue Ge, Xuemei Yao, Liqi Li, Junxia Min, Menghuan Li (), Zhong Luo () and Fudi Wang ()
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Xijiao Ren: Chongqing University
Rui Xue: Chongqing University
Yan Luo: Chongqing University Cancer Hospital
Shuang Wang: Chongqing University
Xinyue Ge: Chongqing University
Xuemei Yao: Chongqing University
Liqi Li: Army Medical University
Junxia Min: Zhejiang University School of Medicine
Menghuan Li: Chongqing University
Zhong Luo: Chongqing University
Fudi Wang: Zhejiang University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-24

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49482-9

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