Low-liver-accumulation lipid nanoparticles enhance the efficacy and safety of HPV therapeutic tumor vaccines.

BACKGROUND: Lipid nanoparticles (LNPs) hold significant potential in vaccine and cancer therapy, but conventional LNPs often cause hepatotoxicity and reduced efficacy due to liver accumulation. METHODS: LNP molecules with varying tail lengths were synthesized in vitro. Transfection efficiency was assessed in vitro via flow cytometry. The BALB/c model was used to evaluate in vivo delivery efficiency of the LNPs. The C57BL/6 mouse model was used to evaluate in vivo anti-tumor pharmacodynamics, along with tumor-infiltrating immune cells and serum inflammatory cytokines. The Sprague Dawley (SD) rat model was used for toxicity testing of the candidate LNP. RESULTS: Lipid 7 demonstrated threefold higher mRNA expression efficiency at the injection site while minimizing liver retention. In an HPV tumor model, Lipid 7 achieved tumor suppression comparable to SM-102-based LNP but outperformed in remodeling the tumor microenvironment (dendritic cells: 12.1% vs. 5.1%; natural killer cells: 1.1% vs. 0.5%) and elevating serum immune cytokines (TNF-α, IL-1β, etc., 1.2-1.8-fold higher). Critically, Lipid 7 reduced off-target mRNA accumulation in the heart, liver, spleen, lungs, and kidneys, mitigating hepatotoxicity risks associated with traditional LNPs. CONCLUSIONS: By employing a novel, non-patented ionizable lipid design, this work balances delivery efficiency and biosafety, Lipid 7 offers a high-efficacy, low-toxicity therapeutic strategy for HPV-related cancers.