Infected cutaneous lesions present significant therapeutic challenges in daily medical practice, especially when complicated by antimicrobial-resistant pathogens. The progressive microenvironment of non-healing lesions combines bacterial invasion with persistent, destructive oxidative stress. Consequently, conventional antimicrobial dressings often fail to coordinate pathogen eradication with tissue regeneration. Recent breakthroughs in nanozyme wound healing provide an innovative solution to this clinical dilemma. By exploiting artificial catalytic frameworks, scientists have created biomimetic structures that dynamically adapt to the evolving biochemical state of damaged skin.

The Challenge of Drug Resistance in Chronic Wounds

Bacterial contamination severely disrupts the physiological repair sequence in acute and chronic skin injuries. Microorganisms colonize the wound bed and rapidly synthesize dense biofilms. These biofilms protect bacterial colonies from systemic antibiotics and host immunological responses. Furthermore, persistent bacterial proliferation sustains a highly acidic microenvironment that recruits non-resolving inflammatory cascades. Neutrophils and pro-inflammatory macrophages continuously generate reactive oxygen species to destroy invading microbes. However, this indiscriminate oxidative barrage damages delicate granulation tissue and degrades vital extracellular matrix proteins. Therefore, standard topical agents often prove insufficient because they fail to resolve secondary oxidative toxicity. Clinicians require advanced therapeutic platforms that can simultaneously eradicate drug-resistant pathogens and attenuate destructive inflammatory signals.

CoNi-MOF Architecture and Catalytic Modulation

To overcome these clinical barriers, researchers synthesized a bimetallic cobalt-nickel metal-organic framework with multi-enzyme catalytic behavior. This engineered structure integrates distinct transition metal centers into an ordered, highly porous crystalline lattice. Specifically, the cooperative electronic interactions between cobalt and nickel optimize the d-band center of cobalt. This electronic modulation shifts the d-band closer to the Fermi level than observed in corresponding monometallic materials. Consequently, the modified electronic density lowers the reaction energy barriers required for surface chemical transformations. In addition, the unique architecture substantially facilitates substrate adsorption across active catalytic domains. Through this atomic-level coordination, the bimetallic framework exhibits enhanced multienzyme-like performance, combining oxidase, peroxidase, and catalase functionalities.

pH-Responsive Antibacterial Nanozyme Wound Healing

The primary advantage of this catalytic framework lies in its autonomous responsiveness to local pH gradients. Infected cutaneous wounds typically exhibit an acidic milieu driven by bacterial metabolism and tissue hypoxia. Under these low pH conditions, the bimetallic framework selectively activates its oxidase-like and peroxidase-like catalytic pathways. Consequently, the material catalyzes the production of potent reactive oxygen species directly adjacent to colonizing bacteria. These localized radicals destroy bacterial membranes, oxidize intracellular proteins, and disrupt established biofilms without inducing drug resistance. The nanozyme wound healing strategy therefore achieves rapid bactericidal efficacy against multidrug-resistant isolates. Because this oxidative burst remains localized, it limits collateral damage to surrounding healthy parenchymal tissue.

Antioxidant Switching and Extracellular Matrix Restoration

As the catalytic system eliminates the bacterial burden, the local wound microenvironment gradually returns toward physiological neutrality. Remarkably, the CoNi-MOF platform self-adapts its enzymatic behavior to mirror this microenvironmental transition. Once the wound bed reaches a neutral pH, the framework suppresses its radical-generating pathways and activates catalase-like activity. Furthermore, the material acquires potent radical scavenging capabilities that rapidly decompose harmful hydrogen peroxide into water and molecular oxygen. This enzymatic shift quickly neutralizes excessive reactive oxygen species and halts oxidative damage to fibroblasts. As a result, the dressing alleviates pathological inflammation and protects newly deposited extracellular matrix components. This autonomous transition eliminates the need for repeated, invasive dressing adjustments during clinical care.

Immunomodulatory Repolarization of Macrophages

Beyond direct antimicrobial and antioxidant actions, the bimetallic nanozyme exerts profound immunomodulatory control over local host defenses. Macrophages demonstrate notable phenotypic plasticity during cutaneous regeneration, transitioning from a pro-inflammatory M1 phenotype to a pro-healing M2 state. However, chronic infection stalls macrophages in the destructive M1 activation phase. The CoNi-MOF platform interrupts this pathological cycle by resolving local oxidative stress. Consequently, it signals resting immune populations and effectively promotes macrophage polarization toward the pro-regenerative M2 phenotype. These repolarized M2 macrophages secrete essential angiogenic factors, downregulate pro-inflammatory cytokines, and recruit restorative fibroblasts. Preclinical in vivo evaluations confirm that this coordinated immune shift markedly accelerates re-epithelialization, vascular formation, and overall wound closure.

Translational Relevance for Clinical Practice

These findings introduce promising horizons for surgical and dermatological wound care strategies. Currently, managing complex surgical site infections and diabetic ulcers requires aggressive antibiotic regimens and meticulous debridement. Nevertheless, escalating antimicrobial resistance limits the effectiveness of traditional therapeutic protocols. Because this self-adaptive framework operates via physical and catalytic mechanisms, it circumvents classic microbial resistance pathways. Moreover, its autonomous transition from an antimicrobial agent to an anti-inflammatory scaffold matches the biological progression of tissue repair. Future translational research must evaluate long-term metal clearance, local biosafety, and optimal dressing formulations. Ultimately, autonomous catalytic platforms may significantly reduce hospitalizations, mitigate amputation risks, and streamline outpatient chronic wound management.

What is a self-adaptive nanozyme?

A self-adaptive nanozyme is an engineered nanomaterial that mimics natural enzymatic functions while dynamically altering its catalytic activity according to microenvironmental changes. In infected wounds, local pH shifts prompt the nanozyme to generate antimicrobial radicals during infection and subsequently neutralize oxidative stress once the tissue returns toward physiological neutrality.

How does the CoNi-MOF eradicate drug-resistant bacteria?

In acidic infected tissue, the framework activates oxidase-like and peroxidase-like activities. These pathways catalyze the generation of reactive oxygen species directly at the infected site. These radicals break down bacterial membranes, denature essential proteins, and degrade resilient biofilms, eliminating drug-resistant microbes without fostering traditional antimicrobial resistance mechanisms.

Why is M2 macrophage polarization crucial for wound repair?

M2 macrophage polarization is essential because these cells orchestrate the proliferative and remodeling phases of tissue repair. While M1 macrophages drive acute inflammation, M2 macrophages suppress inflammatory cytokines, secrete growth factors, stimulate capillary angiogenesis, and recruit fibroblasts. This coordinated transition enables sustained extracellular matrix deposition and rapid re-epithelialization.

Disclaimer: This content is for informational and educational purposes only... Refer to the latest local and national guidelines for clinical practice.

References

Chen Y et al. A Self-Adaptive CoNi-Based Metal-Organic Framework for Autonomous Antibacterial Efficacy and Anti-Inflammatory Resolution in Accelerated Wound Healing. Adv Healthc Mater. 2026 Oct 15. doi: 10.1002/adhm.71851. PMID: 42876428.

Zhao S et al. Application of metal-organic frameworks in infectious wound healing. J Nanobiotechnology. 2024;22(1):387.

Xue Y et al. Metal-Organic Frameworks and Their Composites for Chronic Wound Healing: From Bench to Bedside. Adv Mater. 2024;36(2):e2302587.