Self-assembly Mn-R837 nanosheet sensitized hollow prussian blue for STING activation and ferroptosis co-enhanced sono-immunotherapy

Promoting the maturation of dendritic cells (DCs) play crucial roles in the effectiveness of activating of adaptive immune response. However, the immunosuppressive tumor microenvironments (TME) are thought to impede DC maturation and inhibit antigen presentation, significantly reducing the therapeutic efficacy of immunotherapy. Herein, to realize the cascade activation of DC maturation, we report the first time the integration of reactive oxygen species (ROS)/ferroptosis-mediated immunogenic cell death (ICD) effect, cGAS-STING activation, and tumor-specific delivery of immune adjuvants. To demonstrate this technique, we utilized FDA-approved hollow Prussian Blue (HPB) with good sonodynamic and chemodynamic activities as the template for the self-assembly of Mn-R837. HPB/Mn-R837 not only possesses enhanced US-activated ROS generation capability owing to the construction of heterojunctions, but also exhibits TME-responsive degradation behaviors, achieving the tumor-specific release of Fe^2 +, Fe³⁺, Mn²⁺, Mn⁴⁺, and R837. HPB/Mn-R837-triggered cascade activation of DC maturation were elucidated, including (1) heterojunction fabrication, GSH consumption, and in-situ CDT co-amplified ROS generation as well as ferroptosis could significantly induce robust ICD effect; (2) activation of the cGAS-STING pathway by the released Mn²⁺ serves to stimulate DC maturation; (3) direct promotion of DC maturation can be achieved by the tumor-specific released R837. As a result, significant antitumor effects have been discovered to completely eradicate primary tumors and effectively inhibit the growth of distant tumors without side effects. This work establishes a novel strategy for the integration of ROS/ferroptosis-induced ICD effect, STING activation, and tumor-specific delivery of immune adjuvants into a single nanostructure for establishing lasting and effective immune responses.