Bimetallic peroxide nanoparticles induce PANoptosis by disrupting ion homeostasis for enhanced immunotherapy

PANoptosis has recently emerged as a potential approach to improve the immune microenvironment. However, current methods for inducing PANoptosis are limited. Herein, through biological screening, the rational use of the nutrient metal ions Cu²⁺ and Zn²⁺ had great potential to induce PANoptosis. Inspired by these findings, we successfully developed hydrazided hyaluronic acid-modified zinc copper oxide (HZCO) nanoparticles as a PANoptosis inducer to potentiate immunotherapy. Bioactive HZCO actively delivered Cu²⁺ and Zn²⁺ while disrupting the cellular intrinsic ion metabolism pathway, resulting in double-stranded DNA release and organelle damage in cancer cells. Simultaneously, this process triggered the formation of PANoptosome and the activation of PANoptosis. HZCO-induced PANoptosis inhibited tumor growth and activated potent antitumor immune response, thereby enhancing the effectiveness of anti-programmed cell death 1 therapy. Overall, our work provides an insight into the development of PANoptosis inducers and the design of synergistic immunotherapy strategies.