SP94‐Functionalized Corosolic Acid Liposomes Enhance Tumor Delivery and Immunomodulatory Remodeling Against Hepatocellular Carcinoma

ABSTRACT

The combination of arsenic trioxide (ATO) and all‐trans retinoic acid (ATRA) achieves synergistic efficacy in acute promyelocytic leukemia, with recent studies revealing its therapeutic potential against hepatocellular carcinoma (HCC). Nonetheless, its application is constrained by inconsistent pharmacokinetics, dense stroma, and an immunosuppressive tumor microenvironment (TME). Herein, an SP94 peptide‐functionalized, cholesterol‐free corosolic acid (CA) liposomes (S‐CALP) was developed to co‐deliver arsenic precipitate and a lipophilic all‐trans retinoic acid derivative (RAD) at an optimal 5:1 synergistic molar ratio. S‐CALP prevented premature leakage under neutral physiological conditions, while triggering an acidity‐responsive arsenic burst and intracellular RAD release upon internalization. Notably, substituting cholesterol with CA endowed S‐CALP with superior membrane fusion capability, enabling enhanced intratumoral accumulation. Together with SP94 functionalization, S‐CALP significantly inhibited HCC cell proliferation and angiogenesis. In vivo, S‐CALP achieved a tumor inhibition rate of 82%, extended median survival to 67.5 days, and effectively remodeled the TME by increasing anti‐tumor immune cell infiltration and reducing immunosuppressive cell populations. Interestingly, unmodified CALP outperformed SP94‐modified cholesterol liposomes (S‐LP), highlighting its superior antitumor efficacy and translational potential. Overall, this cholesterol‐free liposome, featuring highly efficient co‐delivery, improved tumor accumulation, and TME remodeling capacities, provides a promising strategy for synergistic chemo‐immunomodulatory therapy of HCC.