Injectable Responsive Hydrogel Delivery Platform: Enabling High Tissue Penetration and Sonogenetic‐Like Potentiating Anti‐Tumor Immunotherapy

The characteristics of malignant solid tumors with dense extracellular matrix (ECM) and immunosuppressive microenvironment (IME) seriously restrict the high efficacy and precise treatment of tumors, leading to increased susceptibility to malignant recurrence and metastasis. Herein, an ultrasound‐mediated hydrogel delivery platform HA‐F127@Ti‐MOF‐Au/PEG‐TK‐DOX/PFD (abbr. HFTiDP) based on a “sonogenetic‐like technology” is developed, which encapsulates sonosensitizer (Ti‐MOF‐Au), chemotherapeutic prodrug (PEG‐TK‐DOX), and ECM‐solubilizing drug pirfenidone (PFD), to achieve high tissue penetration and endogenous intracellular regulation of IME. More importantly, exogenous ultrasound stimulation combined with a hydrogel delivery platform can affect drug resistance‐related gene/protein expressions and influence signal transduction pathways in the immune microenvironment, leading to promoting TAAs release to activate immunity, achieving high efficacy in either pancreatic or triple‐negative breast cancer (TNBC), and remarkably inhibiting lung metastasis and splenomegaly. Overall, this work provides a novel strategy for an ultrasound‐mediated niche‐like delivery platform that offers high efficacy and biosafety in localized cancer therapy. A “sonogenetic‐like technology” is developed to modulate specific protein/gene expressions, activate the immune system, and precise in situ chemotherapy in the immune microenvironment by using the ultrasound effect combined with a nano‐delivery system.