Mesoporous multimetallic PdPtBi nanozymes target redox imbalance and glutamine deprivation for immuno-chemodynamic therapy.

Therapeutic resistance remains a formidable challenge in oncology, mainly due to the chaotic tumor microenvironment (TME), which drive tumor progression and adaptive resistance via a self-sustaining metabolic-oxidative feedback loop. Herein, a multifunctional nanotherapeutic platform based on PdPtBi multimetallic nanozymes (PPB MMNs) is rationally engineered to address these challenges by simultaneously targeting reactive oxygen species (ROS) modulation and glutamine (Gln) metabolic disruption. Specifically, the PPB MMNs display cascade enzyme-mimicking activities resembling peroxidase (POD), catalase (CAT), and glutathione oxidase (GOD-SH). These activities effectively promote the generation of reactive oxygen species (ROS) and facilitate the decomposition of endogenous H₂O₂ into O₂, thereby alleviating hypoxia and inducing oxidative stress. Upon ultrasound (US) activation, their catalytic performance is further amplified, enabling deep-tissue therapeutic efficacy. Concurrently, PPB MMNs impair Gln metabolism, aggravating redox dyshomeostasis and undermining tumor metabolic flexibility. Both in vitro and in vivo studies validate the superior antitumor activity of PPB MMNs in suppressing primary and metastatic tumor growth by disrupting the redox-metabolic axis. Collectively, our study offers a robust framework for designing multimodal nanomedicines that reprogram the TME and overcome resistance, opening new avenues for precise, synergistic cancer therapy based on redox and metabolic vulnerabilities.