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α-GalCer-LNP ehanced mRNA delivery and activates natural killer T cells for superior tumor immunotherapy

Kexin Zhang,Zhen Xu,Zexiu Xiao,Fei Cao,Jing Wang,Yuandong Xu,Winson M.J. Ma,Sihui Long,Gao-Feng Zha

Lipid nanoparticles (LNPs) have emerged as a clinically validated platform for cancer immunotherapy; however, challenges remain in optimizing RNA delivery and promoting synergistic immune activation. To address these issues, we developed a modified LNP system that incorporates α-galactosylceramide (α-GalCer), a CD1d-binding glycolipid known to activate invariant natural killer T (iNKT) cells. Through structural optimization, we created the α-GalCer-LNP (G-LNP), which offers three primary advantages over conventional four-component LNPs: (1) enhanced mRNA transfection efficiency due to improved endosomal/lysosomal escape, (2) increased capacity for in vivo DC transfection, leading to robust activation of tumor-specific CD8 + T cells via MHC-I and iNKT cells via the CD1d pathway, and (3) reprogramming of the tumor microenvironment, resulting in a 1.5-fold increase in iNKT cell infiltration and sustained elevation of IFN-γ (>24 h) in lymph nodes. In a TC-1 cervical carcinoma model, G-LNP induced complete tumor regression in 100 % of treated mice (compared to 42.85 % for standard LNP) and provided long-term protection against tumor rechallenge (lasting >100 days). Mechanistic studies showed that G-LNP preferentially targets CD11c +  DC in the lymph nodes, facilitating coordinated antigen presentation and innate immune activation. This five-component engineering strategy establishes a versatile platform to enhance the functionality of LNPs for the development of next-generation cancer vaccines.