Key Takeaways & Executive Findings
- •• • Inorganic biomaterials exhibit dual immunomodulatory capacities: activation via adjuvant effects, ICD induction, and metabolic reprogramming; suppression via ROS scavenging and modulation of inflammatory cells, with specific examples including nano-ceria-loaded Mg-Al layered double hydroxide for rheumatoid arthritis therapy (Adv Sci, 2024, 11: 2307094). • • ROS-scavenging capabilities are demonstrated by ultrathin hafnium disulfide (HfS2) atomic crystals with colon-targeting for inflammatory bowel disease treatment (ACS Nano, 2022, 16: 15026–15041), indicating precise elimination of excessive ROS to restore immune tolerance. • • Photothermal regulation of macrophage polarization using 2D Ti3C2Tx MXene nanosheets enhances immunomodulatory osteogenesis (Colloid Interface Sci Commun, 2023, 56: 100733), showing that inorganic materials can direct immune cell fate for tissue regeneration. • • Tumor microenvironment-activated nanocomposite for self-amplifying chemodynamic/starvation therapy enhanced IDO-blockade tumor immunotherapy (Adv Sci, 2023, 10: 2303580) demonstrates integration of catalytic activity and immune checkpoint blockade, addressing low tumor immunogenicity and immunosuppressive TMEs.
Abstract
Precise regulation of the immune system is essential for maintaining physiological homeostasis and treating disease. Insufficient immune activation leads to tumor development, whereas excessive immune responses cause autoimmune diseases or chronic inflammation. Inorganic biomaterials, owing to their unique intrinsic properties such as enzyme-mimicking catalytic functions, tunable composition and morphology, degradability, and inherent bioactivity, have transformed from conventional carriers into versatile platforms capable of actively regulating immune responses. This review summarizes recent progress in immunoregulatory inorganic biomaterials, highlighting their dual capacities to induce immune activation or immune suppression. For immune activation, inorganic materials serve as adjuvants to enhance antigen presentation, induce immunogenic cell death (ICD), and reprogram immune cell metabolism, enabling applications in tumor treatment. For immune suppression, specific inorganic materials effectively eliminate excessive reactive oxygen species (ROS), modulate the functions of inflammatory cells such as neutrophils, and promote the development of immunosuppressive cell populations, including regulatory T cells and M2 macrophages, thereby re-establishing immune tolerance in autoimmune diseases. Despite remaining challenges in mechanistic verification, long-term biosafety, and clinical translation, inorganic biomaterials offer a promising multifunctional platform for achieving precise immune interventions across cancer immunotherapy, tissue regeneration, and autoimmune disease management.
1. Introduction
Conventional immunotherapies face critical bottlenecks: low tumor immunogenicity, immunosuppressive tumor microenvironments, and poor bioavailability of therapeutic agents. Organic polymeric and hybrid materials, often used as delivery vehicles, suffer from batch-to-batch variability, structural instability, and insufficient functional persistence in complex biological environments. These limitations hinder precise immune modulation required for effective cancer immunotherapy and autoimmune disease management.
Inorganic biomaterials offer a paradigm shift due to their intrinsic enzyme-mimicking catalytic activities, tunable physicochemical properties, and inherent bioactivity. They can actively regulate immune responses through dual strategies: activation for tumor treatment and suppression for autoimmune diseases. This review systematically analyzes recent advances, focusing on mechanistic pathways and material design, to address the urgent need for innovative platforms capable of finely tuning immune status.
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SI Xinghui, LU Yuhui, ZHA Zhengbao (2026). Inorganic Biomaterials as Immunomodulators: Dual Strategies for Activation and Suppression. SCIENCE CHINA Materials. https://doi.org/10.1007/s40843-025-4001-x
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Frequently Asked Questions
What are the specific catalytic mechanisms by which inorganic biomaterials induce immunogenic cell death (ICD) in tumors?
Inorganic materials such as iron oxide nanoparticles can catalyze Fenton reactions to generate hydroxyl radicals, inducing oxidative stress and ICD. For example, tumor microenvironment-activated nanocomposites for chemodynamic therapy produce ROS to trigger ICD and enhance IDO-blockade immunotherapy (Adv Sci, 2023, 10: 2303580).
How do inorganic biomaterials achieve selective ROS scavenging without disrupting normal cellular redox signaling?
Materials like ceria nanoparticles and hafnium disulfide (HfS2) exhibit enzyme-mimicking activities (e.g., catalase-like, superoxide dismutase-like) that scavenge excessive ROS. Ultrathin HfS2 atomic crystals with colon-targeting capabilities effectively reduce ROS in inflammatory bowel disease models (ACS Nano, 2022, 16: 15026–15041), indicating selective action in inflamed tissues.
What are the long-term biosafety concerns for inorganic biomaterials in clinical translation?
Concerns include potential accumulation in organs, chronic inflammation, and unknown degradation products. For instance, the review notes remaining challenges in long-term biosafety and clinical translation, emphasizing the need for thorough in vivo toxicity studies and biodegradable designs.
Can inorganic biomaterials be engineered to switch between immune activation and suppression based on the disease context?
Yes, by tuning composition, surface chemistry, and external stimuli (e.g., pH, enzymes, light), materials can be designed for context-dependent activity. For example, photothermal regulation with MXene nanosheets can polarize macrophages to M2 phenotype for osteogenesis (Colloid Interface Sci Commun, 2023, 56: 100733), while other materials can induce M1 polarization for tumor therapy.
What is the industrial scalability of these inorganic biomaterials compared to organic polymer-based systems?
Inorganic materials often benefit from well-established synthesis methods (e.g., sol-gel, hydrothermal) and high batch-to-batch consistency. However, challenges include controlling size and surface functionalization at scale. The review does not provide specific cost data, but the intrinsic stability of inorganic materials may reduce formulation complexity.
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