A trimodal combination therapy utilizing cryogel microparticles for hepatocellular carcinoma

Transarterial chemoembolization (TACE) efficacy against hepatocellular carcinoma remains significantly limited by heterogeneous vascularization and intrinsic chemoresistance. The pro-angiogenic cascade orchestrating residual tumor survival, neovascularization, and immunosuppression post-TACE provides a compelling rationale for developing precision locoregional molecular targeted embolization systems. Herein, we fabricated cryogel microparticles (denoted as SQAP) through the complexation of sodium alginate and quaternized chitosan, with simultaneous loading of anlotinib hydrochloride (AL3818) and black phosphorus nanosheets. Physicochemical characterizations verified that SQAP enabled photothermal-responsive release of AL3818 under near-infrared (NIR) irradiation. In vivo evaluations demonstrated that NIR-assisted SQAP triggered efficient tumor cell death and inhibited angiogenesis. They remodeled the immunosuppressive tumor microenvironment via a trimodal combination therapy encompassing molecular targeted, mild photothermal, and embolization therapies. Consequently, these NIR-assisted SQAP cryogel microparticles represent a promising clinical strategy for treatment-refractory hepatocellular carcinoma.