Hierarchical engineering of mesoporous polydopamine for "homologous targeting-cascade blasting" biomimetic phototheranostic nanotrident.

The activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway represents a promising strategy for eliciting host immune responses to eradicate tumors. However, the clinical application of STING agonists is severely hindered by the tumor immunosuppressive microenvironment (TIME) and non-specific delivery. Herein, a biomimetic phototheranostic nanotrident (mPDXZ@M) is meticulously designed through hierarchical engineering of mesoporous polydopamine (mPDA). Upon near-infrared laser irradiation, mPDA-mediated photothermal therapy (PTT) evokes robust cell apoptosis and immunogenic cell death, thereby ameliorating the TIME and triggering ATP secretion for Zn2+ and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) release. The Zn2+ then inhibits glycolysis, lowering heat shock protein 70 and sensitizing tumors to PTT. Ultimately, DMXAA activates the cGAS-STING pathway to promote dendritic cell maturation and cytotoxic T cell infiltration, collectively driving potent tumor regression. Overall, this tailor-engineered phototheranostic nanotrident exemplifies a transformative strategy for self-amplified photo-immunometabolic therapy, enabling effective immune priming and pronounced tumor suppression.