For decades, biomaterials in medicine were conceived as inert scaffolds or passive delivery vehicles, designed to ferry drugs to their targets while provoking as little immune reaction as possible. That paradigm has inverted. The review highlights how materials spanning inorganic nanoparticles, synthetic polymers, natural biomacromolecules, and cell-derived vesicles are now deliberately designed to engage and reprogram macrophages, dendritic cells, T lymphocytes, and innate lymphoid cells. Because these materials can act as immune activators or suppressors depending on their chemistry, size, shape, and context, they offer a versatile platform for treating inflammation, cancer, infection, and autoimmune disease. The authors emphasize that targeted drug delivery and immuno-engineering are only part of the story; the intrinsic immunomodulatory properties of the materials themselves must not be overlooked.

Inorganic nanomaterials occupy a prominent place in this landscape because of their superior physicochemical stability and controllability. Their non-self nature means the immune system recognizes them as foreign, activating phagocytic cells such as macrophages and dendritic cells. While this inflammatory response would be undesirable in healthy tissue, it can paradoxically enhance tumor immunotherapy. Gold nanorods, fullerene derivatives, and graphene oxide derivatives have all demonstrated capacity as vaccine adjuvants, inducing localized inflammation that strengthens immune protection against viral infections and malignancies. A particularly intriguing subset, known as nanozymes, exhibits intrinsic enzyme-like catalytic activity whose output depends on particle size, structure, cellular internalization, and environmental pH, allowing them to either raise or lower reactive oxygen species concentrations in chronic inflammatory microenvironments.

Iron oxide nanoparticles illustrate the clinical maturity of this approach. Several formulations have already been approved by the U.S. Food and Drug Administration as magnetic resonance imaging contrast agents, treatments for iron deficiency, and components of nano-vaccine platforms. Beyond these established uses, studies show that iron oxide nanoparticles can drive M1 polarization of macrophages, boosting production of reactive oxygen species, tumor necrosis factor-alpha, and nitric oxide to inhibit tumor progression. In one reported mechanism, uptake of these particles by macrophages raises intracellular iron and activates the NF-κB signaling pathway, triggering TNF-α-mediated immune activation. The particles also display enzyme-like behavior: ultrasmall Fe₃O₄ nanoparticles act as peroxidases under acidic conditions, decomposing hydrogen peroxide into hydroxyl radicals that kill cancer cells, while a catalase-mimicking material called fenozyme has reduced mortality in experimental cerebral malaria by lowering reactive oxygen levels and promoting macrophage polarization.

Manganese-based nanomaterials have emerged as equally potent immunological tools. Manganese ions markedly enhance the sensitivity of the cGAS–STING pathway, a central innate immune sensor that recognizes microbial and endogenous DNA. Research cited in the review shows that Mn²⁺ increases antigen presentation by dendritic cells and macrophages, facilitating activation of natural killer cells and T lymphocytes, and that combining this effect with anti-PD-1 checkpoint blockade yields notable therapeutic efficacy. Researchers have also developed coordination nanoparticles that self-assemble from manganese ions and a STING agonist, producing enhanced interferon responses and robust antitumor immunity in treatment-resistant tumor models, and manganese-based nano-vaccines have shown promise in preclinical models of SARS-CoV-2 infection. Other metal systems extend the catalog: nanoscale titanium dioxide with nanospike structures exerts mechanical stress on phagocytosing immune cells, triggering potassium efflux and inflammasome activation, while ultrasmall copper oxide nanozymes scavenge reactive oxygen species and ameliorate acute liver injury, diabetic wounds, and acute kidney injury.

Silicon nanoparticles tell a story of transformation from hazard to therapeutic. Unmodified silica can provoke inflammatory responses through interactions with monocytes and the complement system, and accumulation of silica dioxide particles in lung tissue has been shown to create a premetastatic niche in healthy mice. Yet in tumor-bearing organisms this immunostimulatory character becomes an asset. Ultrasmall silica nanoparticles can initiate T cell activation through direct particle–cell interactions in a dose-dependent manner, and certain formulations have progressed to human clinical trials. Hollow mesoporous silica nanoparticles function as immunoadjuvants that enhance both Th1 and Th2 responses, elevate effector memory T cell populations in the bone marrow, and, remarkably, when administered intraperitoneally, significantly improve the response to PD-1 checkpoint blockade by targeting tumor-associated macrophages, activating the Toll-like receptor 4–NF-κB cascade, and increasing secretion of T cell–recruiting chemokines. For immunologically cold tumors, this strategy of amplifying local inflammation is compelling.

Carbon-based nanomaterials present a more complicated picture. Graphene oxide acts as a natural antioxidant, reducing reactive oxygen species in macrophages and mitigating M1 polarization, and graphene quantum dots have suppressed Th1/Th17 polarization, promoted regulatory T cell ratios, and alleviated intestinal inflammation in murine models of enteritis. These quantum dots can even cross the blood–brain barrier and inhibit aggregation of alpha-synuclein fibrils, suggesting neuroprotective potential in Parkinson’s disease. However, concerns about carcinogenicity, particularly for carbon nanotubes, temper enthusiasm; prolonged exposure to multiwalled carbon nanotubes has been reported to intensify the invasiveness of implanted breast cancer cells and promote lung colonization. This duality, in which the same inflammatory capacity that makes a material a useful adjuvant can also pose long-term risks, remains one of the field’s central unresolved problems.

Organic and cell-derived biomaterials offer biocompatibility advantages that inorganic systems struggle to match. Synthetic polymer hydrogels have been engineered to initiate type-2 adaptive immune responses that promote skin regeneration, and acid-responsive polymeric nanoparticles that target lymph nodes and activate the STING pathway have spawned optimized, degradable successors. Cationic nanoparticles composed of PLGA–PDMA block copolymers can scavenge cell-free DNA, reducing inflammatory activation in rheumatoid arthritis models. Natural biomacromolecules carry inherent activity: fungal polysaccharides, yeast cell wall beta-glucans, and hyaluronic acid all modulate macrophage polarization and T cell responses, with hyaluronic acid’s effects shifting depending on molecular weight. DNA nanostructures built through programmable base pairing can deliver CpG oligonucleotides, potent Toll-like receptor 9 agonists, into immune cells with high specificity, and a rectangular DNA origami nanorobot decorated with immune agonists has trafficked to draining lymph nodes and evoked durable tumor-specific immune responses. Perhaps most striking are cell membrane-coated nanoparticles: mesenchymal stem cell membranes displaying PD-L1 have suppressed excessive T cell activation and eased immune-related adverse events from checkpoint blockade, macrophage membrane nanosponges have sequestered inflammatory cytokines in atherosclerosis and sepsis models, and fusion nanodecoys combining ACE2-expressing membranes with monocyte membranes have simultaneously neutralized virus and absorbed cytokines in COVID-19 research. Exosomes, the nanoscale vesicles cells use to communicate, add another layer, with phenotype-dependent functions ranging from tumor repolarization to insulin sensitization.

The review’s authors are candid about the obstacles standing between laboratory promise and clinical routine. Incomplete degradation, unintended biodistribution, and persistent low-grade inflammation may lead to fibrosis, granuloma formation, or off-target immunotoxicity, demanding long-term in vivo studies and standardized evaluation protocols. Inorganic materials raise questions about ion release and oxidative stress during degradation, while polymers suffer from batch-to-batch variability and complex manufacturing that hinders scalability. Exosome production remains inefficient and heterogeneous, and endotoxin contamination, even at trace levels, can confound experimental results entirely. Looking forward, the authors point to single-cell sequencing, spatial transcriptomics, and artificial intelligence-driven material screening as technologies that could illuminate how biomaterials shape immune microenvironments and accelerate rational design. They also envision personalized immunomodulatory biomaterials tailored to individual immune profiles, and feedback-responsive systems capable of achieving controlled, localized, transient immune activation without systemic toxicity. If those challenges can be met, the materials described in this synthesis may do more than carry the next generation of immunotherapies; they may become the therapies themselves, precisely engineered to teach the immune system when to fight and when to stand down.

Subject of Research: Immunomodulatory biomaterials for immunotherapy

Article Title: Advances and projects of immunomodulatory biomaterials used for immunotherapy

Article References: Frumento, D., & Patra, N. (2026). Advances and projects of immunomodulatory biomaterials used for immunotherapy. Holistic Integrative Oncology, 5(1), Article 78. https://doi.org/10.1007/s44178-026-00296-3

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00296-3

Keywords: immunomodulatory biomaterials, immunotherapy, nanozymes, iron oxide nanoparticles, manganese adjuvants, STING pathway, mesoporous silica nanoparticles, graphene quantum dots, cell membrane-coated nanoparticles, exosomes, macrophage polarization, cancer immunotherapy