Key Takeaways & Executive Findings
- •• • Metal ions act as dynamic signaling molecules via non-covalent interactions, enabling rapid immune modulation; this contrasts with stable covalent modifications, offering reversible control for therapeutic intervention. • • Metal-based nanomaterials, such as Fe-Ce6 nanoparticles, achieve bacterial microenvironment-responsive nanozyme generation and photodynamic antibacterial activity, accelerating infected wound healing (Sci China Mater, 2025, 68: 2962–2972). • • Copper ionophores combined with autophagy interference amplify cuproptotic stress and antitumor immunity, as demonstrated in J Control Release (2025, 388: 114262), highlighting a dual-mechanism strategy. • • Magnesium-based nanoflowers in controlled-release hydrogels synergize immunomodulation and cartilage regeneration in tendon-bone healing (Bioactive Mater, 2024, 36: 62–82), indicating metal-ion delivery systems can address tissue repair bottlenecks.
Abstract
Metalloimmunology, an emerging interdisciplinary field, is reshaping our understanding of the immune system at an unprecedented pace. This review systematically elaborates on the core roles of metal ions as critical signaling molecules and metabolic regulators in both innate and adaptive immunity. Special focus is placed on the molecular mechanisms by which metal ions modulate key immune signaling pathways, as well as their mediation of novel immunogenic cell death modalities including ferroptosis, cuproptosis, and pyroptosis. Furthermore, we comprehensively review innovative metal ion-based therapeutic strategies, encompassing metal nanoadjuvants, metal-organic frameworks and nanozymes, along with their cutting-edge applications in cancer, infectious diseases, autoimmune disorders, and tissue repair. Finally, this review delves into the challenges faced by this field in targeted delivery, biosafety, and clinical translation, and provides an outlook on its future development directions with particular emphasis on the immense potential of precisely regulating metal homeostasis for the treatment of autoimmune diseases.
1. Introduction
Conventional immunotherapies, including checkpoint inhibitors and adoptive cell transfer, exhibit durable responses in only a minority of patients, with primary resistance and acquired resistance limiting efficacy. The tumor microenvironment (TME) imposes metabolic and oxidative barriers that suppress effector immune cells, while systemic toxicity and off-target effects restrict dose escalation. These clinical bottlenecks underscore the need for orthogonal strategies that can reprogram immune cells and the TME with spatial and temporal precision.
Metal ions, as essential cofactors and signaling entities, offer a dynamic and reversible regulatory axis that has been largely underexploited. Their coordination chemistry enables the design of stimuli-responsive nanomaterials that release ions on demand, modulate immunogenic cell death pathways, and engage innate immune sensors. This review synthesizes recent advances in metalloimmunology, focusing on how material engineering—such as metal-organic frameworks, nanozymes, and ion-delivery hydrogels—translates fundamental insights into actionable therapeutic paradigms, addressing the translational gap between metal ion biology and clinical application.
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HE Qian, LI Qian, LUAN Xintong, ZHANG Liyun (2026). Material-Inspired Paradigms in Metalloimmunology: From Fundamental Insights to Therapeutic Intervention. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4062-2
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Frequently Asked Questions
What are the primary failure mechanisms of metal-based immunotherapies under physiological stress, and how do the reviewed delivery systems mitigate them?
Metal-based agents often suffer from premature degradation, off-target ion release, and poor tumor penetration. The reviewed systems employ stimuli-responsive designs, such as bacterial microenvironment-responsive Fe-Ce6 nanoparticles that generate nanozymes in situ, ensuring localized activity and reduced systemic toxicity (Sci China Mater, 2025, 68: 2962–2972).
How do copper ionophores achieve selective antitumor immunity without inducing systemic cuproptosis?
Copper ionophores are coupled with autophagy interference to amplify cuproptotic stress specifically in tumor cells, as shown in J Control Release (2025, 388: 114262). This dual mechanism enhances immunogenic cell death and antitumor immunity while sparing normal tissues, though precise dosing and targeting remain critical.
What are the scalability and manufacturing challenges for metal-organic framework (MOF)-based nanoadjuvants?
MOF synthesis often requires harsh conditions and organic solvents, complicating scale-up. However, recent advances in aqueous-phase synthesis and continuous-flow methods are improving reproducibility. The review highlights metal-phenolic complexation as a scalable alternative (ACS Nano, 2025, 19: 15055–15068).
Can metal ion delivery systems achieve clinical translation for autoimmune diseases, and what are the key hurdles?
Precise regulation of metal homeostasis holds promise for autoimmune diseases, but targeted delivery to specific immune cell subsets and long-term biosafety remain unresolved. The review emphasizes the need for biodegradable carriers and real-time monitoring to ensure therapeutic windows are maintained.
How do magnesium-based nanoflowers compare to conventional growth factors in cartilage regeneration?
Magnesium-based nanoflowers in hydrogels provide sustained ion release, promoting immunomodulation and cartilage regeneration in tendon-bone healing (Bioactive Mater, 2024, 36: 62–82). Unlike growth factors, they offer cost-effective and stable alternatives, though comparative efficacy and long-term outcomes require further validation.
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