Abstract

Antigen-presenting cells (APCs) mediating phagocytosis of cancer cells, and subsequent sensing of their mitochondrial DNA (mtDNA) to initiate antigen presentation, is the core mechanism and key rate-limiting step of CD47 blockade therapy. Yet, most current CD47-targeted strategies lack modulation on mtDNA sensing. Herein, we propose a strategy leveraging zinc ion (Zn²⁺) overload, which triggers mtDNA release and calreticulin exposure to simultaneously enhance CD47-blockade-mediated phagocytosis and mtDNA sensing. We engineered a minimalist biomineralized nanoparticle, ZnCO₃@BSA/siCD47, in which Zn²⁺ coordinates with bovine serum albumin (BSA) and small interfering RNA (siRNA) to form stable yet dissociable complexes. This design reconciles the need for stable siRNA encapsulation with efficient intracellular release, thereby enabling spatiotemporally potent CD47 silencing and Zn²⁺ overload. In colorectal cancer and melanoma models, ZnCO₃@BSA/siCD47 restored APCs function, increased T cell infiltration, and suppressed tumor growth by up to 93%, offering a promising strategy for augmenting CD47 blockade therapy.