Golgi-targeted clay nanoregulators with spatiotemporal thermal confinement and cascade-amplified antigen delivery for tumor therapy

As a non-invasive tumor therapy, photothermal therapy (PTT) has garnered considerable attention for its controllability, non-drug resistance and precise tumor ablation. However, its efficacy is often hindered by limited photothermal damage resulting from uncontrollable heat transfer distance and weak immune response caused by insufficient antigen presentation, resulting in tumor metastasis. Herein, a chondroitin sulfate-modified Prussian blue-montmorillonite immunoregulator (PM@CS) is developed to enhance both photothermal ablation and immune response. By integrating the tumor cell adhesion of montmorillonite and Golgi-targeting of CS, PM@CS accumulates on the Golgi apparatus of tumor cells, significantly reducing heat transfer distance compared to Prussian blue alone, thereby enhancing photothermal efficacy. Furthermore, the enhanced photothermal damage can effectively interfere with post-translational modification and secretion of metastasis-associated proteins (the expression of GOLPH3 and GOLM1 reduced by 63.4% and 70.3%, respectively). Besides, PM@CS leads to a 3.3-fold increase in dendritic cell maturation (CD80+ and CD86+ populations) and promotes the proliferation of antigen-specific CD4+ and CD8+ T cells, which is related to the immune potentiator property of montmorillonite and facilitates antigen presentation. Notably, the voltage-gated calcium channels (CaV) were upregulated and Ca2+ inflow was enhanced after PM@CS treatment, ultimately activating calcium signaling cascades. This is conducive to amplifying cascade immunotherapy, thus synergistically inhibiting primary tumor growth and lung metastasis.