The impact of matrix stiffness on hepatic cell function, liver fibrosis, and hepatocellular carcinoma-Based on quantitative data.

Over the past few decades, extensive research has explored the development of supportive scaffold materials for in vitro hepatic cell culture, to effectively mimic in vivo microenvironments. It is crucial for hepatic disease modeling, drug screening, and therapeutic evaluations, considering the ethical concerns and practical challenges associated with in vivo experiments. This review offers a comprehensive perspective on hepatic cell culture using bioscaffolds by encompassing all stages of hepatic diseases-from a healthy liver to fibrosis and hepatocellular carcinoma (HCC)-with a specific focus on matrix stiffness. This review begins by providing physiological and functional overviews of the liver. Subsequently, it explores hepatic cellular behaviors dependent on matrix stiffness from previous reports. For hepatic cell activities, softer matrices showed significant advantages over stiffer ones in terms of cell proliferation, migration, and hepatic functions. Conversely, stiffer matrices induced myofibroblastic activation of hepatic stellate cells, contributing to the further progression of fibrosis. Elevated matrix stiffness also correlates with HCC by increasing proliferation, epithelial-mesenchymal transition, metastasis, and drug resistance of HCC cells. In addition, we provide quantitative information on available data to offer valuable perspectives for refining the preparation and development of matrices for hepatic tissue engineering. We also suggest directions for further research on this topic.

Topical Nanoliposomal Collagen Delivery for Targeted Fibril Formation by Electrical Stimulation.

Collagen is a complex, large protein molecule that presents a challenge in delivering it to the skin due to its size and intricate structure. However, conventional collagen delivery methods are either invasive or may affect the protein's structural integrity. This study introduces a novel approach involving the encapsulation of collagen monomers within zwitterionic nanoliposomes, termed Lip-Cols, and the controlled formation of collagen fibrils through electric fields (EF) stimulation. The results reveal the self-assembly process of Lip-Cols through electroporation and a pH gradient change uniquely triggered by EF, leading to the alignment and aggregation of Lip-Cols on the electrode interface. Notably, Lip-Cols exhibit the capability to direct the orientation of collagen fibrils within human dermal fibroblasts. In conjunction with EF, Lip-Cols can deliver collagen into the dermal layer and increase the collagen amount in the skin. The findings provide novel insights into the directed formation of collagen fibrils via electrical stimulation and the potential of Lip-Cols as a non-invasive drug delivery system for anti-aging applications.

Chemically heparinized PEEK via a green method to immobilize bone morphogenetic protein-2 (BMP-2) for enhanced osteogenic activity.

Osseointegration remains one of the major challenges in the success of bone-related implants. Recently, polyetheretherketone (PEEK) has emerged as an alternative material in orthopedic and dental applications due to its bone-mimicking mechanical properties. However, its bioinertness resulting in poor osseointegration has limited its potential application. So, the surface modification of PEEK with bone morphogenetic protein-2 (BMP-2) can be a potential approach for improving osseointegration. In this study, we proposed the chemical modification of heparin onto PEEK through an environmentally benign method to exploit the BMP-2 binding affinity of heparin. The heparin was successfully functionalized on the PEEK surface via a combination of ozone and UV treatment without using organic solvents or chemicals. Furthermore, BMP-2 was efficiently immobilized on PEEK and exhibited a sustained release of BMP-2 compared to the pristine PEEK with enhancement of bioactivity in terms of proliferation as well as osteogenic differentiation of MG-63. The significant synergistic effect of BMP-2 and heparin grafting on osteogenic differentiation of MG-63 was observed. Overall, we demonstrated a relatively safe method where no harsh chemical reagent or organic solvent was involved in the process of heparin grafting onto PEEK. The BMP-2 loaded, heparin-grafted PEEK could serve as a potential platform for osseointegration improvement of PEEK-based bone implants.

Synthesis of Superabsorbent Hydrogels with Predefined Geometries and Controlled Swelling Properties for Versatile 3D Cell Culture Scaffolds.

This research presents a simple but general method to prepare water-soluble-polymer-based superabsorbent hydrogels with predefined microscale geometries and controlled swelling properties. Unlike conventional hydrogel preparation methods based on bulk solution-phase cross-linking, poly(vinyl alcohol) is homogeneously mixed with polymer-based cross-linkers in the solution phase and thermally cross-linked in the solid phase after drying; the degree of cross-linking is modulated by controlling the cross-linker concentration, pH, and/or thermal annealing conditions. After the shape definition process, cross-linked films or electrospun nanofibers are treated with sulfuric acid to weaken hydrogen bonds and introduce sulfate functionality in polymer crystallites. The resultant superabsorbent hydrogels exhibit an isotropic expansion of the predefined geometry and tunable swelling properties. Particularly, hydrogel microfibers exhibit excellent optical transparency, good biocompatibility, large porosity, and controlled cell adhesion, leading to versatile 3D cell culture scaffolds that not only support immortalized cell lines and primary neurons but also enable stiffness-modulated cell adhesion studies.

Emerging drug delivery systems with traditional routes - A roadmap to chronic inflammatory diseases.

Inflammation is prevalent and inevitable in daily life but can generally be accommodated by the immune systems. However, incapable self-healing and persistent inflammation can progress to chronic inflammation, leading to prevalent or fatal chronic diseases. This review comprehensively covers the topic of emerging drug delivery systems (DDSs) for the treatment of chronic inflammatory diseases (CIDs). First, we introduce the basic biology of the chronic inflammatory process and provide an overview of the main CIDs of the major organs. Next, up-to-date information on various DDSs and the associated strategies for ensuring targeted delivery and stimuli-responsiveness applied to CIDs are discussed extensively. The implementation of traditional routes of drug administration to maximize their therapeutic effects against CIDs is then summarized. Finally, perspectives on future DDSs against CIDs are presented.

ROS-responsive PEGylated ferrocene polymer nanoparticles with improved stability for tumor-selective chemotherapy and imaging.

Ferrocene-based nanoparticles have garnered interest as reactive oxygen species (ROS)-responsive nanocarriers of anticancer drugs and imaging agents. However, their biomedical applications remain limited due to their poor physiological stability. PEGylation of nanocarriers improves their stability and biocompatibility. In this study, we aimed to develop novel PEG-ferrocene nanoparticles (PFNPs) with enhanced stability and ROS responsiveness for the delivery of paclitaxel (PTX) and imaging agents. PEGylation improved the stability of ferrocene nanoparticles, inhibiting their ROS-responsive destruction. Several PEG-ferrocene polymers containing different molar ratios of methacrylic acid and poly (ethylene glycol) methyl ether methacrylate was designed for optimization. ROS-responsive polymers with optimal monomer ratios were self-assembled into PFNPs with enhanced stability. The PFNPs distended, effectively releasing encapsulated PTX and imaging agents within 8 h in the presence of ROS. Furthermore, they remained stable, with no changes in their hydrodynamic diameters or polydispersity indexes after storage in an aqueous solution and biological buffer. The accumulation of PFNPs in a tumor model in vivo was 15-fold higher than a free dye. PTX-loaded PFNPs showed a substantial tumor-suppression effect, reducing tumor size to approximately 18% of that in the corresponding control group. These findings suggest a promising application of ROS-responsive PFNPs in tumor treatment as biocompatible nanocarriers of anticancer drugs and imaging agents.

Novel Application of NIR-I-Absorbing Quinoidal Conjugated Polymer as a Photothermal Therapeutic Agent.

Conjugated polymer nanoparticles (CP NPs) that could absorb the first near-infrared (NIR-I) window have emerged as highly desirable therapeutic nanomaterials. Here, a quinoidal-conjugated polymer (QCP), termed PQ, was developed as a novel class of therapeutic agents for photothermal therapy (PTT). Owing to its intrinsic quinoid structure, PQ exhibits molecular planarity and π-electron overlap along the conjugated backbone, endowing it with a narrow band gap, NIR-I absorption, and diradical features. The obtained PQ was coated with a poly(ethylene glycol) (PEG) moiety, affording nanosized and water-dispersed PQ nanoparticles (PQ NPs), which consequently show a high photothermal conversion efficiency (PCE) of 63.2%, good photostability, and apparent therapeutic efficacy for both in vitro and in vivo PTTs under an 808 nm laser irradiation. This study demonstrates that QCPs are promising active agents for noninvasive anticancer therapy using NIR-I light.

Self-assembled hemin-conjugated heparin with dual-enzymatic cascade reaction activities for acute kidney injury.

Nanozymes have prominent catalytic activities with high stability as a substitute for unstable and expensive natural enzymes. However, most nanozymes are metal/inorganic nanomaterials, facing difficulty in clinical translation due to their unproven biosafety and limited biodegradability issues. Hemin, an organometallic porphyrin, was newly found to possess superoxide dismutase (SOD) mimetic activity along with previously known catalase (CAT) mimetic activity. However, hemin has poor bioavailability due to its low water solubility. Therefore, a highly biocompatible and biodegradable organic-based nanozyme system with SOD/CAT mimetic cascade reaction activity was developed by conjugating hemin to heparin (HepH) or chitosan (CS-H). Between them, Hep-H formed a smaller (<50 nm) and more stable self-assembled nanostructure and even possessed much higher and more stable SOD and CAT activities as well as the cascade reaction activity compared to CS-H and free hemin. Hep-H also showed a better cell protection effect against reactive oxygen species (ROS) compared to CS-H and hemin in vitro. Furthermore, Hep-H was selectively delivered to the injured kidney upon intravenous administration at the analysis time point (24 h) and exhibited excellent therapeutic effects on an acute kidney injury model by efficiently removing ROS, reducing inflammation, and minimizing structural and functional damage to the kidney.

Heparin-Based Hydrogel Micropatches with Human Adipose-Derived Stem Cells: A Promising Therapeutic Approach for Neuropathic Pain Relief.

This study explores the therapeutic efficacy of heparin-based hydrogel micropatches containing human adipose-derived stem cells (hASCs) in treating neuropathic pain caused by nerve damage. Our results showed that hASCs exhibited neuroregenerative and pain-relieving effects when used with heparin-based hydrogel micropatches in the neuropathic pain animal model. The use of this combination also produced enhanced cell viability and nerve regeneration. We conducted various neurological behavioral tests, dynamic plantar tests, histological examinations, and neuroelectrophysiological examinations to confirm the therapeutic effect. Our findings suggest that this approach could maximize therapeutic efficacy and improve the quality of life for patients suffering from neuropathic pain.

Cellular infiltration in an injectable sulfated cellulose nanocrystal hydrogel and efficient angiogenesis by VEGF loading.

BACKGROUND: Cellular infiltration and angiogenesis into implanted biomaterial scaffolds are crucial for successful host tissue integration and tissue regeneration. Cellulose nanocrystal (CNC) is a nano-sized cellulose derivative, which can form an injectable physical gel with salts. Sulfate groups of sulfated CNC (CNC-S) can act as a binding domain to various growth factors and cytokines with a heparin-binding domain for sustained release of them. Vascular endothelial growth factor (VEGF) can promote the proliferation of endothelial cells and angiogenesis. In this study, VEGF-loaded CNC-S hydrogel was evaluated as an injectable scaffold that can induce cellular infiltration and angiogenesis. METHODS: CNC-S was hydrolyzed to get desulfated CNC (CNC-DS), which was used as a negative control group against CNC-S. Both CNC-S and CNC-DS hydrogels were prepared and compared in terms of biocompatibility and VEGF release. The hydrogels with or without VEGF loading were subcutaneously injected into mice to evaluate the biocompatibility, cellular infiltration, and angiogenesis induction of the hydrogels. RESULTS: Both hydrogels possessed similar stability and shear-thinning behavior to be applicable as injectable hydrogels. However, CNC-S hydrogel showed sustained release (until 8 weeks) of VEGF whereas CNC-DS showed a very fast release of VEGF with a large burst. Subcutaneously injected CNC-S hydrogel showed much enhanced cellular infiltration as well as better biocompatibility with milder foreign body response than CNC-DS hydrogel. Furthermore, VEGF-loaded CNC-S hydrogel induced significant angiogenesis inside the hydrogel whereas VEGF-loaded CNC-DS did not. CONCLUSION: CNC-S possesses good properties as a biomaterial including injectability, biocompatibility, and allowing cellular infiltration and sustained release of growth factors. VEGF-loaded CNC-S hydrogel exhibited efficient angiogenesis inside the hydrogel. The sulfate group of CNC-S was a key for good biocompatibility and the biological activities of VEGF-loaded CNC hydrogel.

The effect of the surface coating of human adipose-derived stem cells by various GAGs on the biodistribution of them upon intravenous administration.

Glycosaminoglycans (GAGs) are essential for cell-cell and cell-ECM interactions. Unique structures of GAGs provide high affinities to specific cell receptors. Especially, hyaluronic acid (HA), chondroitin sulfate (CS), and heparin are known to have affinities to the liver sinusoidal endothelial cells (LSECs), so they have been utilized as a ligand for liver targeting nanoparticle systems. In this study, we compared different GAGs as a targeted cell delivery ligand by using lipid-conjugated GAGs. Conjugated lipids of GAGs could provide a stable coating over 2 days on the surface of human adipose-derived stem cells (hADSCs) by physical insertion. The hADSCs coated by different GAGs were intravenously injected into mice, and the biodistribution of cells was analyzed by an In Vivo Imaging System (IVIS) to compare the effect of various GAGs on the modulation of biodistribution of stem cells. The results showed that all three GAGs could provide less entrapment in the lung but enhanced accumulation in the liver and spleen. Especially, HA- and heparin coating on hADSCs showed a 1.5-fold higher accumulation than CS-coating on hADSCs in the liver and spleen. Thus, lipid-conjugated HA and heparin are potentially useful coating materials for the liver or spleen-targeted delivery system of therapeutic stem cells.

Nanoreactor for cascade reaction between SOD and CAT and its tissue regeneration effect.

Nanoreactors for scavenging reactive oxygen species (ROS), a major factor in inflammatory diseases, can reduce overproduced ROS, and thus can prevent further progress of the diseases or facilitate the regeneration of damaged inflamed tissues. Herein, we designed a pluronic-based nanocarrier loaded with dual antioxidant enzymes present in vivo (superoxide dismutase (SOD) and catalase (CAT)) as a nanoreactor system for the regeneration of inflammatory tissue. The catalytic activity of each enzyme was enhanced by loading it into the nanocarrier. More importantly, the nanocarrier could enhance the cascade reaction between SOD and CAT, which converts the superoxide anion to oxygen. The synergistic anti-inflammatory effect of the nanoreactor based on the cascade reaction was verified in vitro. Furthermore, in an inflammatory bowel disease (IBD) mouse model, the dual enzyme (SOD/CAT)-loaded nanocarrier could result in significantly enhanced tissue regeneration and notably alleviated inflammation activities upon intravenous administration of them compared to other control groups, including single enzyme (SOD or CAT)-loaded nanocarrier and the free mixture of both enzymes without the nanocarrier. Thus, the efficacy of the nanoreactor for the cascade reaction on tissue regeneration in vivo was proved. Accordingly, the nanoreactor could be applied for tissue regeneration therapy against various inflammatory diseases.

Mesenchymal stem cell-encapsulated cellulose nanofiber microbeads and enhanced biological activities by hyaluronic acid incorporation.

Cell microencapsulation is a process to entrap viable and functional cells within a biocompatible and semi-permeable matrix to provide a favorable microenvironment to the cells. Cellulose nanofiber (CNF), a low-cost and sustainable cellulose-derived natural polymer, has been studied as a matrix for 3D stem cell culture in the form of a bulk hydrogel. Here, the preparation of CNF microbeads for the long-term 3D culture of human adipose-derived stem cells (hADSCs) was demonstrated. Furthermore, hyaluronic acid (HA) was physically incorporated into the stem cell encapsulated CNF microbeads with various molecular weights and concentrations to investigate its potential in enhancing the cellular bioactivities. The beneficial effects of HA incorporation on encapsulated cells were significant compared to CNF microbeads, especially with 700 kDa molecular weight and 0.2% in concentration in terms of cell proliferation (~2 times) and VEGF secretion (~2 times) while maintaining their stemness. All the results demonstrated that the HA-incorporated CNF microbeads could serve as a promising microencapsulation matrix for hADSCs.

All-in-one nanosponge with pluronic shell for synergistic anticancer therapy through effectively overcoming multidrug resistance in cancer.

Overexpression of P-glycoprotein (P-gp) on cancer cells is a major hurdle to effectively treat tumors with multidrug resistance (MDR). The current study aimed to explore anticancer drug and P-gp inhibitor delivery as a promising strategy to efficiently treat colorectal cancer with MDR. To this end, a multidrug-loaded all-in-one nanosponge (ANS) was developed to simultaneously deliver doxorubicin (DOX), paclitaxel (PTX), and the P-gp inhibitor tetrandrine (TET), referred to as DOX/PTX/TET@ANS, without chemical conjugation. ANS with high loading content and efficiency facilitated a pH-dependent and controlled release with different profiles. Compared to free drugs and DOX/PTX@ANS, DOX/PTX/TET@ANS exhibited more effective anticancer effects on P-gp-overexpressing colorectal cancer cells and solid tumor mouse xenografts, without major toxicity. Notably, ANS composed of pluronic shell induced in vitro P-gp inhibition compared to TET, implying a synergistic anticancer effect. These findings suggest that ANS can encapsulate multiple drugs to efficiently deliver chemotherapy, particularly in MDR tumors.

Effective and prolonged targeting of a nanocarrier to the inflammation site by functionalization with ZnBPMP and chitosan.

Efficient and selective targeting of inflamed tissues/organs is critical for diagnosis and therapy. Although nanomaterials themselves have an intrinsic advantage due to their size for targeting inflammation sites, additional functionalization of the nanomaterials with proper targeting moieties is desired to enhance the targeting efficiency. In this study, we aimed to improve the inflammation targeting characteristics of a pluronic-based nanocarrier, which has advantages as a nanosized delivery cargo for diverse molecules, by conjugating with chitosan and ZnBPMP (two Zn(II) ions chelated 2,6-bis[(bis(2-pyridylmethyl)amino)-methyl]-4-methylphenol) moiety. Specific and significant cellular uptake and interaction between the nanocarrier functionalized with ZnBPMP ligand and chitosan to an apoptosis-induced immune cell line were observed in vitro. An inflammation model in the mouse ear caused by skin hypersensitivity was used to evaluate the effect of functionalization with chitosan and ZnBPMP moiety by comparing with various control groups. Functionalization of the nanocarrier with chitosan greatly enhanced the in vivo circulation time of the nanocarrier, so prolonged targeting ability of the nanocarrier to the inflamed ear was achieved. Additional ZnBPMP functionalization to chitosan-functionalized nanocarrier also resulted in significantly improved initial targeting and further enhancement in the targeting until 5 days to the inflamed ear and the decreased non-specific accumulation of the nanocarrier to the remaining body. Thus, developed nanocarrier has a high potential as a drug delivery carrier as well as a diagnostic agent to the inflammation sites.

Nanozyme Impregnated Mesenchymal Stem Cells for Hepatic Ischemia-Reperfusion Injury Alleviation.

Mesenchymal stem cell (MSC) based therapy holds great potential for treating numerous diseases owing to their capability to heal injured tissue/organs through paracrine factors secretion and immunomodulation. Despite the high hopes, the low viability of transplanted cells in the injured tissues due to the elevated oxidative stress levels remains the largest obstacle in MSC-based cell therapy. To achieve desired therapeutic efficiency, the survival of the transplanted MSCs in the high oxidative stress environment needs to be ensured. Herein, we proposed the use of a ROS-scavenging nanozyme to protect transplanted MSCs from oxidative stress-mediated apoptosis and thereby improve the therapeutic effect. Prussian blue (PB) nanoparticles as a biocompatible ROS-scavenging nanozyme were incorporated into the MSCs without affecting the stemness and differentiation potential of MSCs. The nanozyme impregnation significantly improved the survival of MSCs in a high oxidative stress condition as well as augmented their paracrine effect and anti-inflammatory properties, resulting in a profound therapeutic effect in vivo in the liver ischemia-reperfusion (I/R) injury animal model. Our results indicated that the nanozyme incorporation into MSCs is a simple but efficient way to improve the therapeutic potential of MSC-based cell therapy.

Enhanced Transport and Permeation of a Polymeric Nanocarrier across the Retina by Mixing with ATP upon Intravitreal Injection.

The outer part of the retina pigment epithelium (RPE) in the retina is the main site of neovascularization associated with retinal diseases. However, various obstacles interrupt the delivery of medicines across the RPE, mainly due to the well-developed tight junctions in the RPE. Currently, there is no practical formulation to overcome this issue. In this study, we demonstrated that simple mixing with adenosine tetraphosphate (ATP) has the potential to greatly enhance the transport and permeation of a polymeric nanocarrier across the retina via intravitreal administration. Chitosan-functionalized, pluronic-based nanocarrier (NC), which can deliver various biomolecules efficiently, was used as a polymeric nanocarrier. Mixing with ATP facilitated the diffusion of the nanocarrier in the vitreous humor by reducing the electrostatic interaction between NC and negatively charged glycosaminoglycans (GAGs) in the vitreous humor. Mixing with ATP also allowed the penetration of NC across the whole retina, and it resulted in a great increase (approximately nine times) in the transport of NC across the retina, as well as spreading it throughout the whole retina upon intravitreal administration in a mouse model. This enhanced permeation across the retina was specific to ATP but not to GTP, suggesting the possibility of P2Y receptor-mediated tight junction disruption by ATP.

Effect of C-terminus Conjugation via Different Conjugation Chemistries on In Vivo Activity of Albumin-Conjugated Recombinant GLP-1.

Glucagon-like peptide-1 (GLP-1) is a peptide hormone with tremendous therapeutic potential for treating type 2 diabetes mellitus. However, the short half-life of its native form is a significant drawback. We previously prolonged the plasma half-life of GLP-1 via site-specific conjugation of human serum albumin (HSA) at position 16 of recombinant GLP-1 using site-specific incorporation of p-azido-phenylalanine (AzF) and strain-promoted azide-alkyne cycloaddition (SPAAC). However, the resulting conjugate GLP1_8G16AzF-HSA showed only moderate in vivo glucose-lowering activity, probably due to perturbed interactions with GLP-1 receptor (GLP-1R) caused by the albumin-linker. To identify albumin-conjugated GLP-1 variants with enhanced in vivo glucose-lowering activity, we investigated the conjugation of HSA to a C-terminal region of GLP-1 to reduce steric hindrance by the albumin-linker using two different conjugation chemistries. GLP-1 variants GLP1_8G37AzF-HSA and GLP1_8G37C-HSA were prepared using SPAAC and Michael addition, respectively. GLP1_8G37C-HSA exhibited a higher glucose-lowering activity in vivo than GLP1_8G16AzF-HSA, while GLP1_8G37AzF-HSA did not. Another GLP-1 variant, GLP1_8A37C-HSA, had a glycine to alanine mutation at position 8 and albumin at its C-terminus and exhibited in vivo glucose-lowering activity comparable to that of GLP1_8G37C-HSA, despite a moderately shorter plasma half-life. These results showed that site-specific HSA conjugation to the C-terminus of GLP-1 via Michael addition could be used to generate GLP-1 variants with enhanced glucose-lowering activity and prolonged plasma half-life in vivo.

A long-term stable paper-based glucose sensor using a glucose oxidase-loaded, Mn2BPMP-conjugated nanocarrier with a smartphone readout.

A simple paper-based analytical device (PAD) for the one-pot detection of glucose was developed herein using an artificial peroxidase-functionalized and glucose oxidase (GOx)-loaded pluronic-based nanocarrier (PNC). Mn2BPMP (BPMP; 2,6-bis[(bis(2-pyridylmethyl)amino)-methyl]-4-methylphenolate), an artificial peroxidase, was conjugated to PNC, allowing GOx to be loaded with a very high encapsulation efficiency. In solution, Mn2BPMP-PNC showed higher peroxidase-like catalytic efficiency than did Mn2BPMP at physiological pH. In addition, glucose detection via enzyme cascade reaction between GOx and Mn2BPMP in the GOx loaded-Mn2BPMP-PNC was more sensitive than the simple combination of Mn2BPMP and GOx with excellent selectivity. Subsequently, a PAD was fabricated using a laser printer with an assay substance containing GOx loaded-Mn2BPMP-PNC and peroxidase chromogenic substrate. The prepared Mn2BPMP-PNC-based PAD quantitatively measured glucose in human serum ranging from normal levels to those typical for diabetics as well as in buffer by obtaining RGB (red, green, and blue) color values through smartphone readout or the naked eye. Importantly, the present PNC-based PAD maintained the detection efficiency during storage at room temperature for 6 weeks in contrast to the rapid decrease in detection efficiency obtained for PAD containing Mn2BPMP and GOx without PNC.

Antioxidant and anti-inflammatory activities of Prussian blue nanozyme promotes full-thickness skin wound healing.

Excessive reactive oxygen species (ROS) and unresolved inflammations are the major causes of impaired wound healing as they overwhelm the cellular antioxidant system and impede the healing process. In this study, we examined the application of Prussian blue (PB) nanozyme as a novel material for cutaneous wound healing through the alleviation of excessive ROS and inflammation modulation. The PB nanoparticles not only exhibited hydrogen peroxide (H2O2) degradation activity but also showed strong superoxide scavenging ability. PB nanozyme mitigated the intracellular ROS at a high oxidative stress environment, resulting in a pronounced cytoprotective effect. Moreover, PB nanozyme also displayed significant anti-inflammatory activity, as evident from the suppression of inflammatory mediators in the lipopolysaccharide (LPS) induced macrophage cells. Encouraged by the in vitro results, we evaluated the in vivo therapeutic efficacy of PB nanozyme in a full-thickness cutaneous wound model combined with LPS treatment to mimic bacterial infection. The beneficial effects of topically applied PB nanozyme on wound healing and tissue regeneration were evident compared to the control. The periodical administration of a low amount (50 µg × 4) of PB nanoparticles exhibited faster wound closure as well as collagen deposition, maturation, and organization. Moreover, the PB treatment effectively induced the differentiation of keratinocytes, enhanced the neovascularization, and reduced macrophage burden in the entire wound site. Thus, PB nanozyme not only accelerated the healing process in an infection-mimicking cutaneous wound model but also exhibited tissue regeneration characteristics owing to the synergistic effect of ROS-scavenging and anti-inflammatory activities.