The clinical stakes are enormous. Diabetic foot ulcers alone affect more than 18 million people each year, and anyone with diabetes faces a lifetime risk of developing one between 19 and 34 percent. Once an ulcer appears, recurrence rates climb as high as 65 percent within five years, and roughly one in five patients ultimately requires amputation. The reason these wounds refuse to heal lies in a self-reinforcing pathological loop: persistent infection by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa, which form antibiotic-resistant biofilms; a flood of pro-inflammatory cytokines including TNF-α, IL-1β, and IL-6 that traps the wound in its inflammatory phase; and a diabetic microenvironment marked by hyperglycemia, oxygen starvation, and destructive oxidative stress that degrades the extracellular matrix and blocks the migration of the fibroblasts and keratinocytes needed to close the wound.

Metal-based nanozymes attack this loop from multiple directions at once. These nanoparticles, built from metals or metal oxides such as cerium dioxide, iron oxide, and molybdenum disulfide, mimic the activity of natural enzymes like peroxidase, superoxide dismutase, and catalase. A copper-based nanozyme, for example, can exploit the Cu+/Cu2+ redox cycle to perform double duty: in the acidic conditions of an acute infection it behaves like a peroxidase, converting hydrogen peroxide into bactericidal hydroxyl radicals that shred biofilms, while in the alkaline environment of a chronic non-healing wound it switches to catalase-like behavior, decomposing hydrogen peroxide into oxygen to relieve tissue hypoxia. The same released copper ions then stabilize HIF-1α, the master regulator of the hypoxic response, driving vascular endothelial growth factor expression and new blood vessel growth even without low oxygen.

The review catalogs how each metal brings a distinct therapeutic personality. Zinc-based nanozymes suppress the NF-κB inflammatory pathway and disrupt bacterial membranes while supporting the matrix metalloproteinases that remodel healing tissue. Iron-based systems use Fenton chemistry to induce ferroptosis in bacteria and senescent cells, and can dampen the TGF-β/Smad signaling that fuels scar formation. Silver combines ion-mediated bacterial killing with photothermal therapy that penetrates biofilms. Magnesium degrades into ions that neutralize wound acidity and activate the Wnt/β-catenin pathway implicated in hair follicle regeneration. Manganese nanozymes generate oxygen from endogenous hydrogen peroxide while scavenging the superoxide radicals produced during ischemia-reperfusion injury. Cerium dioxide stands out for its self-regenerating Ce3+/Ce4+ antioxidant cycle, which can continuously neutralize reactive oxygen species without being consumed.

What elevates the field beyond simple chemistry is the growing mastery of structure-activity relationships. The review details how shrinking particles below five nanometers produces quantum confinement effects that unlock enzyme activities absent in larger particles; ultrasmall gold nanoclusters, for instance, display superoxide dismutase activity that bulk gold lacks. Single-atom nanozymes, in which isolated metal atoms are anchored into coordination sites such as Fe-N4 on nitrogen-doped carbon, achieve complete atomic utilization and catalytic activities orders of magnitude higher than their nanoparticle counterparts, closely mimicking the active centers of natural metalloenzymes. Shape matters too: cerium oxide nanorods expose high-energy crystal facets with lower oxygen vacancy formation energies than spherical particles, two-dimensional nanosheets eliminate diffusion limits by exposing nearly all their atoms, and hollow nanocages act as nanoreactors that concentrate substrates and dramatically amplify reaction rates.

In diabetic wound models, these design principles converge on striking results. One copper-based hydrogel system switches its dominant enzyme activity based on wound pH, killing bacteria in acidic conditions and promoting angiogenesis in alkaline ones. Iron-based dual-nanozyme cascades consume glucose to starve bacteria while generating hydroxyl radicals, a “starvation-enhanced chemodynamic” strategy that also lowers local blood sugar. Platinum systems automatically shift from ROS-generating sterilization in the early hypoxic phase to oxygen-producing repair as inflammation subsides. Multimetallic platforms push further: an Au-Cu aerogel with four enzyme-mimicking activities supplies its own hydrogen peroxide and oxygen, while an ultrasound-activated Cu-Au-L-arginine system runs a five-enzyme cascade covering ROS regulation, oxygenation, glucose control, and nitric oxide-driven angiogenesis. Some of the newest devices even integrate real-time glucose and pH monitoring into self-powered patches that use the generated electric field to stimulate keratinocyte migration.

Perhaps most provocatively, the review documents evidence that nanozymes can push healing past mere closure toward regeneration of skin appendages, the hair follicles, sebaceous glands, and sweat glands whose loss is what separates a scar from true skin. Cerium dioxide nanozymes delivered by microneedle patches outperformed minoxidil in animal models of androgenetic alopecia, clearing ROS around follicles while the microneedles themselves triggered Wnt/β-catenin activation. Nickel-copper bimetallic nanozymes co-delivered with minoxidil achieved 83.4 percent transdermal efficiency and restored follicular stem cell proliferation by generating oxygen in situ. In wound models not designed to study hair at all, researchers repeatedly observed unexpected follicle and sweat gland regrowth, including in a cerium-based hydrogel treated diabetic wound study where RNA sequencing revealed abundant appendage formation alongside complete closure, likely driven by Wnt ligands secreted by M2-polarized macrophages.

On scarring, the review identifies molybdenum, zirconium, and cerium systems as the most promising anti-fibrotic agents. A molybdenum-based nanoscaffold with SOD and GPx-like activity blocks the ROS-TGF-β1 feedback loop by preventing oxidation of the latency-associated peptide that releases active TGF-β1, and metabolomic analysis showed it starves myofibroblasts of the glycine and glutamate raw materials needed for collagen triple helix assembly. Zirconium-doped Prussian blue nanozymes reprogram macrophages toward the anti-inflammatory M2 phenotype while preserving mitochondrial function, and a tannic acid-modified cerium hydrogel spray normalized collagen organization to resemble healthy skin architecture. The authors caution, however, that indiscriminate ROS scavenging can backfire, since reactive oxygen species serve as essential signaling molecules in early healing, and that current studies often cannot distinguish genuine anti-fibrotic reprogramming from the passive benefit of faster wound closure.

The path to the clinic remains steep. No metal nanozyme drug has yet received FDA approval for dermatological use, and only one nanozyme therapeutic has entered clinical trials, a Phase II nanozyme-hydrogel dressing for diabetic wounds. Biosafety concerns differ sharply by context: on open wounds, nanoparticles can translocate into the bloodstream and accumulate in the liver and spleen, silver carries the risk of permanent argyria, copper has a narrow therapeutic window before triggering cuproptosis, and manganese poses neurotoxicity at relatively low exposure thresholds. The safest candidates are those the body already knows how to handle, iron and zinc, which enter endogenous metabolic pools, and molybdenum, which oxidizes into non-toxic molybdate ions that the kidneys readily excrete. Regulatory ambiguity compounds the problem, since a catalytic nanozyme may be classified as a drug while the same material in a dressing may be treated as a device, and manufacturing consistency at kilogram scale, particularly for single-atom architectures, remains a formidable engineering challenge.

The review’s authors frame the future in terms of a shift from material-centric to pathology-centric design: sequential therapies that deploy copper or silver for initial debridement and then cerium or manganese for remodeling, stimuli-responsive systems that switch from bacterial killing to tissue repair as the wound environment changes, and next-generation platforms that combine nanozymes with stem cell niches, gene delivery, and smart bioelectronic dressings. If the field can solve its biosafety and manufacturing bottlenecks, metal-based nanozymes may finally deliver what chronic wound patients have awaited for decades, not just closed skin, but skin that works.

Subject of Research: Metal-based nanozymes for skin regeneration, chronic wound healing, anti-scarring therapy, and hair follicle restoration

Article Title: Skin regeneration axis under metal-based nanozymes: from chronic wound healing to structural and functional restoration

Article References: Zhuang, Z.-M., Guo, K., Wu, Z.-R., Wang, Y., Zhong, X.-C., Chen, C.-Y., Feng, Z.-X., Yu, Y.-Z., Zhang, H.-Q., Tan, M.-H., Zhang, T., Lin, X.-Y., Wang, Y., & Tan, W.-Q. (2026). Skin regeneration axis under metal-based nanozymes: from chronic wound healing to structural and functional restoration. Journal of Advanced Research, 88, 1013-1043. https://doi.org/10.1016/j.jare.2026.01.068

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.01.068

Keywords: nanozymes, skin regeneration, chronic wounds, diabetic foot ulcers, wound healing, scarring, hair regeneration, reactive oxygen species, nanomedicine, biofilms, cerium dioxide, regenerative medicine