Nat. Commun. 10, 574 (2019)

The liver is characterized by a highly immunosuppressive environment, which hampers the successful application of immunotherapies against tumour and metastasis development. Since a major role in liver immunoregulation is played by liver sinusoidal epithelial cells (LSEC), modulating their activity through targeted intervention might improve the success of immunotherapies. Towards this end, it has been shown that α-melittin, a cationic peptide endowed with immunomodulatory properties and tumour cell cytotoxicity, has a signature sequence that recognizes LSEC. However, delivered as free drug, it causes haemolysis.

Now, Yu et al. show that a self-assembled α-melittin-based lipid nanoparticle can be injected intravenously with reduced side effects and delivered specifically to LSEC, where it triggers molecular processes that eventually modulate the liver’s immunological state. Using different in vivo models, the researchers show that treatment with the nanoparticle prolongs the animals’ survival, induces anti-tumour immune memory and reduces the number of metastases without compromising liver functions. In particular, in a spontaneous liver metastastic model, 80% of the animals survive and are metastasis-free 100 days after primary tumour resection, in contrast to 20% in controls.