Harnessing PD-1-overexpressing macrophage membrane for preparation of lenvatinib-loaded vesicles to boost immunotherapy against HCC recurrence after radiofrequency ablation

Hepatocellular carcinoma (HCC) is characterized by high malignancy, high recurrence rate and poor prognosis. Radiofrequency ablation (RFA) is the first-line curative treatment for early-stage HCC. Yet, effective inhibition of local recurrent HCC is still challenging because of immunosuppressive tumor microenvironment (TME) and upregulation of multiple tyrosine kinase receptors in the post-RFA residual tumor. The combination of tyrosine kinase inhibitor lenvatinib and immune checkpoint blockade (ICB) therapy is a promising strategy to tackle HCC, but the limited bioavailability and weak targeting still restrict the therapeutic effect. Inspired by the predominant proinflammatory stress reaction and infiltration of macrophages in the TME of residual HCC after RFA, we developed a lenvatinib-loaded hybrid nanovesicles (PML@Len) consisting of lipid and engineered macrophage membrane overexpressing programmed cell death protein 1 (PD-1). The incorporation of macrophage membrane prevented PML@Len from being phagocytosed by kupffer cells. The replenished PD-1 not only facilitated tumor accumulation but also blocked programmed cell death ligand 1(PD-L1) overexpressed on the tumor. Additionally, delivery of lenvatinib by PML@Len resulted in effective anti-angiogenesis and regulation of immunosuppressive TME to boost anti-tumor immunity. Consequently, these hybrid nanovesicles based on engineered macrophage membrane demonstrated great potency to elicit anti-tumor memory effects of T lymphocytes, hence effectively suppressing the tumor recurrence after RFA.