Bimetallic peroxide nanoparticles induce PANoptosis by disrupting ion homeostasis for enhanced immunotherapy
Guanghui Hou, Youdong Chen, Huali Lei, Yu‐Ling Lu, Lin Liu, Zhihui Han, Shumin Sun, Jingrui Li, Liang Cheng
Abstract
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 Cu 2+ and Zn 2+ 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 Cu 2+ and Zn 2+ 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.