Single‐Dose TACE‐Like Injection of Sustained‐Release Panobinostat/IL‐12 Polymeric Microparticles is Effective in Preclinical Liver Cancer Models

ABSTRACT Background & Aims : Primary liver cancer is the third leading cause of cancer death worldwide, and about 70% of hepatocellular carcinomas (HCCs) do not respond to systemic immunotherapies. Transarterial chemoembolization (TACE) remains standard treatment for intermediate‐stage HCC, but long‐term survival is poor. We aimed to develop a polymeric TACE‐like platform to sensitize liver cancer to checkpoint inhibitors by enabling sustained co‐delivery of panobinostat and IL‐12. Methods : Patient‐derived liver cancer organoids were used to screen drugs and identify panobinostat as a cytotoxic agent. We then formulated sustained‐release microparticles from anionic poly(lactic‐co‐glycolic acid) (PLGA) and cationic poly(beta‐amino ester) (PBAE) for combined delivery of panobinostat and IL‐12, and tested the system in three liver cancer models. Results : The microparticles achieved tumor‐specific retention and sustained release for two weeks following a single intratumoral or intrahepatic arterial injection. This led to tumor inhibition and prolonged survival in orthotopic liver cancer models. Mechanistically, treatment promoted tertiary lymphoid structure formation, increased infiltration of immune cells, and elevated pro‐inflammatory cytokines, triggering innate and adaptive antitumor immune responses. Conclusions : A PLGA/PBAE sustained‐release microparticle platform was successfully developed for TACE‐like co‐delivery of panobinostat and IL‐12. This combined chemoimmunotherapy strategy shows promise for overcoming immune suppression and improving liver cancer treatment.