Intrahepatic targeting and sustained release of a Toll like receptor 8 agonist enhances hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) remains a major global health challenge with limited therapeutic options. Liver-resident Kupffer cells, which exhibit strong phagocytic activity and predominantly adopt an immunosuppressive M2 phenotype in the tumor microenvironment, not only promote tumor immune escape but also rapidly clear conventional drug delivery systems, posing a fundamental barrier to effective treatment. Herein, we present a novel strategy that uses these cells as both barriers and therapeutic anchors. We developed a CD47-mimetic self-peptide-modified liposomal system that targets SIRPα on Kupffer cells and delivers the TLR8 agonist ZG0895, currently in clinical trials in the U.S. and China. By activating "don't-eat-me" signaling, the system suppresses phagocytosis, enabling stable surface attachment and sustained release of the agonist for durable immune reprogramming. Importantly, this phagocytosis inhibition establishes a spatiotemporal window that facilitates co-delivery of doxorubicin (DOX) liposomes to HCC cells via GLUT1-mediated targeting, resulting in synergistic immunochemotherapeutic effects. This dual modulation strategy improves targeting precision, treatment durability, and therapeutic synergy, offering a unique intrahepatic approach that addresses key challenges in HCC management and accelerates the clinical translation of TLR8 agonist-based nanomedicines.