Nanoreactor-Enabled PANoptosis via ZBP1 Activation Potentiates Immunotherapy in Non-Small Cell Lung Cancer

Tumor immune microenvironment reconstruction and regulated cell death promotion synergistically enhance treatment outcomes in immunosuppressive non-small-cell lung cancer (NSCLC). PANoptosis, a newly identified form of immunogenic cell death that integrates the essential molecular components of pyroptosis, apoptosis, and necroptosis, elicits robust antitumor immunity via damage-associated molecular pattern (DAMP)-mediated immune activation. Nevertheless, strategies to induce PANoptosis remain underexplored, presenting a critical gap in leveraging its therapeutic potential. Herein, we engineered a multifunctional nanoreactor (Bi@SiO 2 @COP@AQ4N&PTX@hybrid-membrane, BSCAPM) as a PANoptosis inducer by integrating photothermal, photodynamic, chemotherapy, and SiO 2 -mediated biological effects. The nanoreactor features a bismuth-based core for photothermal functionality, in conjunction with a SiO 2 layer and a drug-loaded covalent organic polymer (COP) nanoplatform that synergistically disrupts mitochondrial homeostasis. In addition, the bioactive nanoparticles mediate co-delivery of paclitaxel and phenoxyanthraquinone, concurrently compromising nuclear DNA superhelical integrity and triggering profound mitochondrial stress culminating in PANoptosome assembly and ZBP1-dependent PANoptosis. In vitro and in vivo studies demonstrated that BSCAPM effectively targeted tumor sites, initiated ZBP1-dependent PANoptosis and elicited a robust immunogenic response, leading to enhanced tumor elimination and lung metastasis restraints. This study not only elucidates the mechanistic basis of BSCAPM-induced PANoptosis but also provides a new strategy for the precise treatment of NSCLC.