Biomineralized OMV-based nanocomposite orchestrates cascade-amplified antitumor immunity via eliciting dual pyroptosis and blocking autophagy.

Apoptosis resistance, the severely immunosuppressive tumor microenvironment (TME), and the self-adaptive survival mechanisms of tumor cells significantly impair the efficacy of tumor therapies, driving us to seek more effective antitumor therapeutics that can induce devastative tumor death modalities. Herein, we present a biomineralized bacterial outer membrane vesicles-based nanocomposite (Gd-ZIF@OMV@DC661) designed to activate pyroptotic dualism while simultaneously blocking the pyroptotic checkpoint. Upon internalization by tumor cells, the nanocomposite undergoes acid-responsive degradation, releasing Zn(2+), Gd(3+), DC661 (a potent autophagy and lysosomal function inhibitor), and exposing OMVs with pyroptotic performance. Cellular oxidative stress induced by Zn(2+) and Gd(3+), in conjunction with lipopolysaccharide (LPS) presented by the outer membrane vesicles (OMVs), activates both caspase-1-dependent canonical and caspase-11-dependent non-canonical pyroptotic pathways. To counteract the tumor's adaptive autophagic mechanisms-known as a pyroptotic checkpoint to suppress pyroptosis, the released DC661 inhibited tumor autophagy, deactivated pyroptotic actuators, amplified tumor pyroptosis, and simultaneously induced lysosomal cell death by causing lysosomal lipid peroxidation, thereby inducing robust immunogenic cell death. The consequent release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) facilitates dendritic cell (DC) maturation and T-cell activation, driving a potent adaptive immune response. Furthermore, the presence of Gd³⁺ allows for real-time tumor tracking via T1-weighted magnetic resonance imaging. Overall, this study presents a multifunctional, theranostic nanoplatform that integrates dual pyroptosis, lysosomal cell death, and immune activation, offering a promising strategy for immune-silent solid tumor treatment.