Injectable HMME‐Loading Emulsion Hydrogel for Ultrasound‐Triggered Release and Enhanced Sonodynamic Immunotherapy

Immune checkpoint blockade (ICB) therapies, such as targeting programmed death-1 (PD-1) and programmed cell death protein ligand-1 (PD-L1), are often ineffective in low-immunogenic tumors, limiting their widespread use. In this study, an emulsion hydrogel is developed to encapsulate the sonosensitizer hematoporphyrin monomethyl ether (HMME), aimed at enhancing sonodynamic immunotherapy for low-immunogenic cancers. The water-in-oil emulsion hydrogel, characterized by its shear-thinning rheological properties, demonstrates excellent ultrasound (US)-triggered and lipase-triggered release, followed by sustained release. The emulsion hydrogel loaded with HMME (Gel@HMME), when combined with US, induces an immune response by promoting dendritic cell (DC) maturation and M1-tumor-associated macrophage (M1-TAM) polarization. This, in turn, enhances the infiltration of helper T lymphocyte 1 (Th1) cells and cytotoxic T lymphocytes (CTLs), thereby amplifying the antitumor immune response. Furthermore, Gel@HMME + US enhances the expression of PD-L1 in tumor cells. The combination of ICB (anti-PD-1, αPD-1) with Gel@HMME + US exerts a significant therapeutic effect on pancreatic cancer by upregulating the expression of calreticulin. Thus, this study presents a promising strategy for treating low-immunogenic cancers using an injectable HMME-loaded emulsion hydrogel, which enhances sonodynamic immunotherapy.