A pyroptosis-enhanced leucocyte-hitchhiking liposomal nanoplatform for potentiated immunotherapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumor with unsatisfactory response to immunotherapy. Pyroptosis, a recently discovered form of regulated cell death (RCD), possesses a huge potential to enhance the immunotherapy efficiency against HCC. To achieve efficient drug delivery and ideal activation of antitumor immunity, an E-selectin modified liposomal nanoplatform co-loading gemcitabine elaidate and BMS-202 (a small molecule programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitor) was designed. Following intravenous injection, the liposomal nanoplatform could efficiently bind to sialylated carbohydrates on the surface of peripheral blood leucocytes via E-selectin, subsequently hitchhiking with leucocytes to realize substantial accumulation in the HCC tissue. After cellular uptake by HCC cells, the released gemcitabine could trigger gasdermin E (GSDME)-dependent pyroptosis with the release of danger-associated molecular patterns (DAMPs) and pro-inflammatory cytokines, thus generating antitumor immunity. The released BMS-202 could further relieve immune suppression by blocking the formation of PD-1/PD-L1 complex. More importantly, gemcitabine-triggered tumor pyroptosis enhanced natural orientation of leucocytes to inflammatory tumor site, further increasing the nanoplatform delivery by facilitating tumor leucocyte infiltration through a positive feedback loop. The in vivo efficacy of the fabricated liposomes demonstrated a favorable antitumor immunity by promoting dendritic cell maturation and T cell activation. In summary, this pyroptosis-enhanced leucocyte-hitchhiking liposomal nanoplatform suggests synergistic antitumor activity and unique ability to modulate drug delivery, showing promise as a highly efficient strategy for potentiated tumor immunotherapy, with a potential for clinical translation.