Electrostatically Assembled CaO2@MPN-HA Nanoreactors Potentiate Anti-PD-1 Therapy in Thyroid Cancer via Synergistic Ferroptosis and Calcium Overload

Immune checkpoint blockade (ICB) therapy has achieved remarkable breakthroughs in clinical cancer treatment; however, its efficacy is often limited by the immunosuppressive characteristics of the tumor microenvironment (TME) and the insufficient infiltration of cytotoxic T lymphocytes. Inducing immunogenic cell death (ICD) to convert “cold tumors” into “hot tumors” is an effective strategy to overcome this barrier. Herein, we propose a new ion-interference immunotherapy strategy based on the synergistic action of “ferroptosis–calcium overload” and construct a multi-responsive nanoreactor (CaO₂@MPN-HA) with a layer-by-layer (LbL) self-assembled architecture. To address the intrinsic electrostatic repulsion between the negatively charged metal–polyphenol network (MPN) and the targeting ligand hyaluronic acid (HA), we innovatively introduce the cationic polymer polyethyleneimine (PEI) as an “electrostatic bridge,” enabling surface charge reversal through electrostatic attraction. This strategy successfully constructs a robust core–shell structure and endows the material with lysosomal escape capability. Upon entering tumor cells, the nano-reactor undergoes responsive disassembly in the acidic and glutathione (GSH)-rich TME, releasing tannic acid to facilitate the reduction of Fe³⁺ to highly active Fe²⁺ and catalyze the efficient Fenton reaction fueled by self-supplied H₂O₂ from the CaO₂ core. Meanwhile, the burst release of Ca²⁺ induces mitochondrial dysfunction and synergistically amplifies oxidative stress. This cascade assault potently triggers ferroptosis-dominated ICD, promoting dendritic cell maturation and effector T-cell infiltration. In a TtT/GF thyroid tumor-bearing mouse model, the combination of CaO ₂ @MPN-HA with anti-PD-1 therapy significantly suppressed primary tumor growth and effectively prevented abscopal effect by activating systemic antitumor immune memory. This work not only provides an efficient “ in situ vaccine” strategy for refractory thyroid cancer but also offers a generalizable materials-science solution to overcome electrostatic repulsion in the interfacial assembly of nanomedicines.