Precursor-Engineering Hierarchical Architecture Nanozymes Loading with Cisplatin for Redox Homeostasis Modulation in Immunotherapy

Tumor immunotherapy exerts transformative effects in cancer treatment by leveraging intrinsic immunity and acting broadly effective across cancers, while first-line chemotherapy plays a direct role by disrupting tumor DNA and reducing burden. However, the clinical utility of immunotherapy is notably constrained by the immunosuppressive tumor microenvironment (ITME), while chemotherapy suffers from intrinsic systemic toxicity and acquired resistance. Herein, multifunctional nanozymes on cerium oxide sacrificial templates were designed via precursor engineering, with zirconium introduced to leverage the Kirkendall effect, whereby differing migration rates of zirconium and cerium ions form hierarchical porous structures. Accordingly, such structural features facilitate efficient mass transfer, thereby notably enhancing their triple enzymatic activity. Hierarchical architectures, coupled with hyaluronic acid moieties, further enable high-capacity cisplatin loading and high-specificity tumor targeting, effectively addressing poor drug delivery and off-target issues. Moreover, ultrasound-amplified redox homeostasis modulation driven by the nanozymes’ enzymatic activity acts as a key regulator for disrupting tumor cell redox balance. Meanwhile, synergy between oxidative stress and cisplatin-induced DNA damage acts as a dual stimulus to intervene in tumor survival pathways, not only reversing ITME but also mitigating chemotherapy-associated limitations, thereby fostering concurrent tumor cell death and immunogenic cell death and consequently highlighting promising prospects for malignancy therapy.