Cascade-amplification of melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies

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. To address these challenges, a cascade-amplification strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) was reported. The liposomes were 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 amplified IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as ATP for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulated MMP-2 expression that combined with released ATP to cause AND-gate activation of ACP, thus triggering the in-situ release of CpG-based immunoadjuvants for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibited tumor-intrinsic ERK1/2-HIF-1α-VEGF 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.