Engineered Nanozymes Reprogram the Colorectal Cancer Microenvironment to Overcome Chemoresistance and Immune Exclusion

Colorectal cancer (搜索)搜索该疾病 (CRC) remains one of the most prevalent and lethal malignancies worldwide, with recent GLOBOCAN estimates indicating over 1.9 million new cases and more than 900,000 fatalities each year, positioning it among the foremost causes of cancer incidence and mortality globally. While immune checkpoint inhibitors have produced sustained clinical responses in microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer, this benefit is confined to a minor genetic subset. Pembrolizumab查看药品详情 markedly improved progression-free survival in MSI-H/dMMR metastatic CRC, yet most patients harbor microsatellite-stable (MSS) tumors that exhibit limited responsiveness to immune checkpoint blockade. These clinical realities underscore the urgent need for CRC-targeted approaches capable of addressing metastatic propagation, chemoresistance, immunological exclusion, and the complex tumor microenvironment (TME).

Catalytic Nanomedicine as a New Therapeutic Paradigm

Catalytic nanomedicine, particularly nanozymes, has emerged as a promising strategy to regulate the aberrant metabolic milieu of malignancies. Unlike natural enzymes, nanozymes exhibit enhanced structural stability, adjustable catalytic activity, and customizable surface chemistry, enabling them to respond to critical features of the CRC microenvironment, including acidic pH, disrupted redox homeostasis, elevated hydrogen peroxide (H2O2), and increased glutathione (GSH) concentrations. Through dynamic catalytic reactions—such as Fenton/Fenton-like processes, amplification of reactive oxygen species (ROS), glutathione depletion, and oxygen regulation—nanozymes can alter tumor metabolic plasticity, induce ferroptotic and apoptotic cell death, and enhance immunological responses.

These attributes confer distinct advantages in transforming "cold" colorectal tumors into an inflamed, immunologically active phenotype, thereby enhancing the effectiveness of both cytotoxic and immunotherapeutic agents. CRC presents a fitting disease context for nanozyme-mediated therapy owing to its distinctive pathological features: a mucin-dense barrier that restricts drug infiltration, a hypoxic and H2O2-abundant TME that fosters oxidative stress resilience and chemotherapy resistance, and a microbiota-influenced immune milieu that facilitates tumor advancement and immune evasion.

Why Conventional Therapies Fall Short

Current CRC management relies predominantly on surgery, radiotherapy, cytotoxic chemotherapy, and molecularly targeted or immune-based therapies, each with inherent constraints. Standard first-line systemic regimens such as FOLFOX, FOLFIRI, and CAPEOX—sometimes combined with anti-VEGF or anti-EGFR antibodies—can shrink tumors transiently and prolong survival, but their efficacy is limited by dose-dependent systemic toxicities and the rapid emergence of multidrug resistance driven by DNA-damage repair, drug efflux pumps, metabolic reprogramming, and epithelial-mesenchymal transition. Radiotherapy, used primarily for local control in rectal cancer, is constrained by normal tissue tolerance and radioresistance due to hypoxia. Immune checkpoint drugs have transformed therapy for a small subset of patients with dMMR or MSI-H CRC, but the bulk of MSS tumors remain "immune cold" with low T-cell infiltration and high levels of immunosuppressive myeloid cells.

Nanozyme Platforms and Catalytic Mechanisms

Nanozymes are artificial enzymes that combine the physicochemical characteristics of nanomaterials with the catalytic activity of natural enzymes. Several platform classes have been explored for CRC therapy. Iron-based nanozymes are central to chemodynamic therapy (CDT) and ferroptosis-based approaches, with their therapeutic effect attributed to reversible Fe2+/Fe3+ redox cycling that triggers Fenton or Haber–Weiss-type reactions to convert TME-resident H2O2 into highly reactive hydroxyl radicals (•OH). Copper-based nanozymes display dual-modal cytotoxicity through peroxidase- and oxidase-like ROS production while also serving as inducers of cuproptosis, a copper-dependent programmed cell-death pathway. Manganese-based nanozymes, such as MnO2 nanostructures, degrade under high GSH and acidic conditions to release Mn2+, depleting GSH and activating the STING (搜索)搜索该靶点 innate-immune pathway to link CDT with immunotherapy.

Metal oxide nanozymes—including Fe3O4, CeO2, and MnO2—offer pH-dependent catalytic behavior. Fe3O4 nanoparticles were the first inorganic materials shown to possess peroxidase-like activity, catalyzing H2O2 efficiently in the mildly acidic CRC TME (pH ≈ 6.5–6.8) while remaining suppressed under neutral physiological conditions, providing intrinsic tumor selectivity. Carbon-based nanozymes, porous framework nanozymes (MOFs and COFs), and single-atom nanozymes round out the design spectrum, each with distinct trade-offs in catalytic efficiency, biocompatibility, degradability, and manufacturability.

Nanozyme-Enhanced Chemotherapy

A defining application of catalytic nanozymes is the augmentation of chemotherapy. Transition metal-based nanozymes catalyze Fenton and Fenton-like reactions to boost intracellular ROS beyond the antioxidant buffering capacity of cancer cells, leading to permanent oxidative injury, mitochondrial membrane potential disruption, cytochrome-c release, and caspase-dependent apoptosis. Concurrently, nanozymes consume GSH through redox cycling, disrupting the GPX4 (搜索)搜索该靶点 pathway and compromising cellular defenses against oxidative stress. Nanozymes can also disrupt multidrug resistance by down-regulating ATP synthesis, blocking ATP-binding cassette transporters, and sensitizing cancer cells to 5-fluorouracil查看药品详情 and oxaliplatin查看药品详情.

A notable example is the Cu-PrIm (搜索)搜索该药品 metal-organic framework (MOF) nanozyme, in which distorted Cu-N4 active centers drive both TME-responsive Cu2+ release and peroxidase-like ROS production. Cu-PrIm exhibits marked peroxidase-like activity with a low Km of 0.18 mM and Vmax of 23.37 × 10−6 M·s−1, alongside potent glutathione oxidase activity. In 5-FU–resistant HCT116 cells (resistance index = 3708), Cu-PrIm markedly reduced HIF-1α (搜索)搜索该靶点 protein stability, causing the IC50 of 5-FU to drop from 4.83 mM to 10.84 μM—a roughly 440-fold reduction—and decreasing the resistance index to 8. In pulmonary metastasis assays, Cu-PrIm reduced both the number and size of metastatic nodules by over 50%. The chemosensitizing effect was validated in patient-derived organoids and patient-derived xenograft (PDX) models, where Cu-PrIm combined with FOLFOXIRI significantly delayed post-treatment regrowth and eliminated drug-tolerant persister cells.

Nanozyme-Mediated Immunomodulation

Beyond chemical sensitization, nanozymes can reconfigure the immunological architecture of CRC. Nanozymes increase ROS generation in tumors, inducing immunogenic cell death (ICD) through calreticulin exposure, ATP release, and high-mobility group box-1 secretion. These danger-associated molecular patterns promote dendritic cell maturation and antigen presentation, ultimately priming cytotoxic T-lymphocytes. Nanozyme-induced redox stress also promotes M1 macrophage polarization while inhibiting tumor-supportive M2 phenotypes, and some nanozymes activate the cGAS–STING (搜索)搜索该靶点 signaling pathway to enhance type-I interferon secretion and systemic antitumor immunity. These immunomodulatory effects sensitize CRC tumors to immune checkpoint blockade, offering a route to extend the benefit of PD-1/PD-L1 inhibitors beyond MSI-H populations.

Nanozyme-Assisted Photothermal Therapy

Many metallic and metal-oxide nanozymes exhibit strong photothermal conversion efficiency, enabling an integrated thermo-catalytic paradigm known as "thermo-Fenton synergy." Photothermal heating disrupts mitochondrial respiration, elevates lipid peroxidation, and facilitates ferroptosis, resulting in dual-mechanism tumor ablation. A Ru@CeO2 core–shell hollow nanozyme demonstrated a photothermal conversion efficiency of 29.4%, elevating solution temperature to approximately 55°C within 7 minutes of 808 nm laser irradiation, while its CeO2 shell provided catalase-like activity to generate oxygen and alleviate tumor hypoxia. In orthotopic CRC models, mice receiving this nanozyme therapy showed near-complete eradication of tumor signal over a 40-day period, with no significant micrometastases detected in common metastatic sites.

Safety, Pharmacokinetics, and Clinical Translation Challenges

Despite promising therapeutic efficacy, the clinical translation of nanozyme-based systems faces substantial hurdles. Major concerns include long-term metal buildup, oxidative toxicity from uncontrolled catalytic reactions, and interactions with the intestinal barrier and gut microbiota. Inappropriate regulation of transition-metal nanozymes may result in partial dissolution or redox cycling, releasing ions that contribute to systemic oxidative stress or local inflammation. Prolonged catalytic activity could lead to low-grade oxidative stress, epithelial barrier breakdown, crypt damage, fibrosis, and chronic intestinal inflammation. Non-specific ROS generation or broad-spectrum antibacterial activity might also destroy beneficial commensal bacteria, diminish short-chain fatty acid synthesis, and exacerbate intestinal inflammation.

Manufacturing requires reliable and scalable synthesis with batch-to-batch consistency, harmonized characterization techniques, good manufacturing practice (GMP)-grade materials, and long-term toxicological investigations to facilitate regulatory alignment. A defining advantage of CRC is its procedural accessibility via endoscopy, which allows localized, image-guided, and repeatable nanozyme activation—turning colonoscopy from a diagnostic tool into a platform for catalytic therapy. Future directions include endoscope-assisted intratumoral injection, rectal gels, muco-inert coatings, and ultrasound fiber activation, as well as artificial intelligence-guided design to optimize catalytic centers, surface ligands, and delivery carriers.