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

Abstract 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.