Bioactive Nanofiber-Hydrogel Composite Regulates Regenerative Microenvironment for Skeletal Muscle Regeneration after Volumetric Muscle Loss.

Volumetric muscle loss (VML) is a severe form of muscle trauma that exceeds the regenerative capacity of skeletal muscle tissue, leading to substantial functional impairment. The abnormal immune response and excessive reactive oxygen species (ROS) accumulation hinder muscle regeneration following VML. Here, an interfacial cross-linked hydrogel-poly(ε-caprolactone) nanofiber composite, that incorporates both biophysical and biochemical cues to modulate the immune and ROS microenvironment for enhanced VML repair, is engineered. The interfacial cross-linking is achieved through a Michael addition between catechol and thiol groups. The resultant composite exhibits enhanced mechanical strength without sacrificing porosity. Moreover, it mitigates oxidative stress and promotes macrophage polarization toward a pro-regenerative phenotype, both in vitro and in a mouse VML model. 4 weeks post-implantation, mice implanted with the composite show improved grip strength and walking performance, along with increased muscle fiber diameter, enhanced angiogenesis, and more nerve innervation compared to control mice. Collectively, these results suggest that the interfacial cross-linked nanofiber-hydrogel composite could serve as a cell-free and drug-free strategy for augmenting muscle regeneration by modulating the oxidative stress and immune microenvironment at the VML site.

Metformin-grafted polycaprolactone nanoscaffold targeting sensory nerve controlled fibroblasts reprograming to alleviate epidural fibrosis.

Epidural fibrosis (EF), associated with various biological factors, is still a major troublesome clinical problem after laminectomy. In the present study, we initially demonstrate that sensory nerves can attenuate fibrogenic progression in EF animal models via the secretion of calcitonin gene-related peptide (CGRP), suggesting a new potential therapeutic target. Further studies showed that CGRP could inhibit the reprograming activation of fibroblasts through PI3K/AKT signal pathway. We subsequently identified metformin (MET), the most widely prescribed medication for obesity-associated type 2 diabetes, as a potent stimulator of sensory neurons to release more CGRP via activating CREB signal way. We copolymerized MET with innovative polycaprolactone (PCL) nanofibers to develop a metformin-grafted PCL nanoscaffold (METG-PCLN), which could ensure stable long-term drug release and serve as favorable physical barriers. In vivo results demonstrated that local implantation of METG-PCLN could penetrate into dorsal root ganglion cells (DRGs) to promote the CGRP synthesis, thus continuously inhibit the fibroblast activation and EF progress for 8 weeks after laminectomy, significantly better than conventional drug loading method. In conclusion, this study reveals the unprecedented potential of sensory neurons to counteract EF through CGRP signaling and introduces a novel strategy employing METG-PCLN to obstruct EF by fine-tuning sensory nerve-regulated fibrogenesis.

Tumor-derived microvesicles for cancer therapy.

Extracellular vesicles (EVs) are vesicles with lipid bilayer structures shed from the plasma membrane of cells. Microvesicles (MVs) are a subset of EVs containing proteins, lipids, nucleic acids, and other metabolites. MVs can be produced under specific cell stimulation conditions and isolated by modern separation technology. Due to their tumor homing and large volume, tumor cell-derived microvesicles (TMVs) have attracted interest recently and become excellent delivery carriers for therapeutic vaccines, imaging agents or antitumor drugs. However, preparing sufficient and high-purity TMVs and conducting clinical transformation has become a challenge in this field. In this review, the recent research achievements in the generation, isolation, characterization, modification, and application of TMVs in cancer therapy are reviewed, and the challenges facing therapeutic applications are also highlighted.

Ag nanocomposite hydrogels with immune and regenerative microenvironment regulation promote scarless healing of infected wounds.

BACKGROUND: Bacterial infection, complex wound microenvironment and persistent inflammation cause delayed wound healing and scar formation, thereby disrupting the normal function and appearance of skin tissue, which is one of the most problematic clinical issues. Although Ag NPs have a strong antibacterial effect, they tend to oxidize and form aggregates in aqueous solution, which reduces their antibacterial efficacy and increases their toxicity to tissues and organs. Current research on scar treatment is limited and mainly relies on growth factors and drugs to reduce inflammation and scar tissue formation. Therefore, there is a need to develop methods that effectively combine drug delivery, antimicrobial and anti-inflammatory agents to modulate the wound microenvironment, promote wound healing, and prevent skin scarring. RESULTS: Herein, we developed an innovative Ag nanocomposite hydrogel (Ag NCH) by incorporating Ag nanoparticles (Ag NPs) into a matrix formed by linking catechol-modified hyaluronic acid (HA-CA) with 4-arm PEG-SH. The Ag NPs serve dual functions: they act as reservoirs for releasing Ag/Ag+ at the wound site to combat bacterial infections, and they also function as cross-linkers to ensure the sustained release of basic fibroblast growth factor (bFGF). The potent antibacterial effect of the Ag NPs embedded in the hydrogel against S.aureus was validated through comprehensive in vitro and in vivo analyses. The microstructural analysis of the hydrogels and the in vitro release studies confirmed that the Ag NCH possesses smaller pore sizes and facilitates a slower, more sustained release of bFGF. When applied to acute and infected wound sites, the Ag NCH demonstrated remarkable capabilities in reshaping the immune and regenerative microenvironment. It induced a shift from M1 to M2 macrophage polarization, down-regulated the expression of pro-inflammatory factors such as IL-6 and TNF-α, and up-regulated the expression of anti-inflammatory IL-10. Furthermore, the Ag NCH played a crucial role in regulating collagen deposition and alignment, promoting the formation of mature blood vessels, and significantly enhancing tissue reconstruction and scarless wound healing processes. CONCLUSIONS: We think the designed Ag NCH can provide a promising therapeutic strategy for clinical applications in scarless wound healing and antibacterial therapy.

An extracellular matrix mimicking alginate hydrogel scaffold manipulates an inflammatory microenvironment and improves peripheral nerve regeneration by controlled melatonin release.

Low efficiency of nerve growth and unstable release of loaded drugs have become a major problem in repairing peripheral nerve injury. Many intervention strategies were focused on simple drug loading, but have still been less effective. The key challenge is to establish a controlled release microenvironment to enable adequate nerve regeneration. In this study, we fabricate a multilayered compound nerve scaffold by electrospinning: with an anti-adhesive outer layer of polycaprolactone and an ECM-like inner layer consisting of a melatonin-loaded alginate hydrogel. We characterized the scaffold, and the loaded melatonin can be found to undergo controlled release. We applied them to a 15 mm rat model of sciatic nerve injury. After 16 weeks, the animals in each group were evaluated and compared for recovery of motor function, electrophysiology, target organ atrophy status, regenerative nerve morphology and relative protein expression levels of neural markers, inflammatory oxidative stress, and angiogenesis. We identify that the scaffold can improve functional ability evidenced by an increased sciatic functional index and nerve electrical conduction level. The antioxidant melatonin loaded in the scaffold reduces inflammation and oxidative stress in the reinnervated nerves, confirmed by increased HO-1 and decreased TNF-α levels in regenerating nerves. The relative expression of fast-type myosin was elevated in the target gastrocnemius muscle. An improvement in angiogenesis facilitates neurite extension and axonal sprouting. This scaffold can effectively restore the ECM-like microenvironment and improve the quality of nerve regeneration by controlled melatonin release, thus enlightening the design criteria on nerve scaffolds for peripheral nerve injury in the future.

Engineered tumor microvesicles modified by SP94 peptide for arsenic trioxide targeting drug delivery in liver cancer therapy.

Liver cancer is among the leading cause of cancer related death worldwide. There is growing interest in using traditional Chinese medicines such as arsenic trioxide (ATO) to treat liver cancer. ATO have attracted attention due to its wide range of anti-cancer activities. However, the current ATO formulations are associated with drawbacks such as short half-life, lack of targeting ability towards solid tumors and apparent toxic side effects. Tumor microvesicles (TMVs) has shown encouraging results for the delivery of drugs to solid tumor. In this work, we designed ATO loaded TMVs further modified by SP94 peptide as liver cancer specific ligand (ATO@SP94-TMVs). This drug delivery system utilized SP94 peptide that selectively targets liver cancer cells while TMVs increase the accumulation of ATO at tumor site and activate immune response owing to the associated antigens. ATO@SP94-TMVs exhibited high encapsulation efficiency and tumor microenvironment triggered enhanced release of ATO in vitro. Cytotoxicity and uptake studies revealed remarkable inhibition and specific targeting of H22 cells. In addition, excellent immune response was detected in vitro, enhancing anti-tumor efficacy. Furthermore, a tumor inhibition rate of about 53.23 % was observed in H22 bearing tumor model. Overall, these results confirm that ATO@SP94-TMVs can be a promising nano drug delivery system for the future liver cancer therapy and improve its clinical applications.

Progress of cell membrane-derived biomimetic nanovesicles for cancer phototherapy.

In recent years, considerable attention has been given to phototherapy, including photothermal and photodynamic therapy to kill tumor cells by producing heat or reactive oxygen species (ROS). It has the high merits of noninvasiveness and limited drug resistance. To fully utilize this therapy, an extraordinary nanovehicle is required to target phototherapeutic agents in the tumor cells. Nanovesicles embody an ideal strategy for drug delivery applications. Cell membrane-derived biomimetic nanovesicles represent a developing type of nanocarrier. Combining this technique with cancer phototherapy could enable a novel strategy. Herein, efforts are made to describe a comprehensive overview of cell membrane-derived biomimetic nanovesicles for cancer phototherapy. The description in this review is mainly based on representative examples of exosome-derived biomimetic nanomedicine research, ranging from their comparison with traditional nanocarriers to extensive applications in cancer phototherapy. Additionally, the challenges and future prospectives for translating these for clinical application are discussed.

Glutaraldehyde modified red blood cells delivering artesunate to the liver as a dual therapeutic and prophylactic antimalaria strategy.

Malaria can spread quickly in the population and develop rapidly. Patients with malaria usually die due to lack of timely and effective treatment. Artesunate (AS) is a highly effective and low-toxicity antimalarial drug, but its short half-life in the blood makes it difficult to control the malaria infection completely. Red blood cells (RBCs) have great biodegradability and can be employed to encapsulate various drugs. In this work, we employed RBCs as carriers to encapsulate AS and modified them with glutaraldehyde to construct an intelligent response drug delivery system (G-AS-RBCs) targeting the liver for antimalaria therapeutic and prophylactic activity. The G-AS-RBCs had a drug loading amount of 6.56 ± 0.14 mg 10-8 cells, suggesting excellent biocompatibility. G-AS-RBCs exhibited strong liver targeting efforts and can be maintained in the mice for at least 9 days, showing the potential for malaria prevention. The enrichment of AS in the liver was enhanced because of the natural liver targeting of erythrocytes and the enhancement of liver targeting by glutaraldehyde treatment. Furthermore, AS entrapped into RBCs also showed improved slow-release characteristics and achieved a better effect of inhibiting or killing the malaria parasite than free drugs. Therefore, this RBC-based strategy is expected to realize the prevention and treatment of malaria and has good application prospects.

A novel fluorinated polyethyleneimine with microRNA-942-5p-sponges polyplex gene delivery system for non-small-cell lung cancer therapy.

Gene delivery for non-small-cell lung cancer treatment has been a challenge due to low nucleic acid binding ability, cell-wall barrier, and high cytotoxicity. Cationic polymers, such as the traditional "golden standard" polyethyleneimine (PEI) 25 kDa have emerged as a promising carrier for non-coding RNA delivery. However, the high cytotoxicity associated with its high molecular weight has limited its application in gene delivery. To address this limitation, herein, we designed a novel delivery system using fluorine-modified polyethyleneimine (PEI) 1.8 kDa for microRNA-942-5p-sponges non-coding RNA delivery. Compared to PEI 25 kDa, this novel gene delivery system demonstrated an approximately six-fold enhancement in endocytosis capability and maintain a higher cell viability. In vivo studies also showed good biosafety and anti-tumor effects, attribute to the positive charge of PEI and the hydrophobic and oleophobic properties of the fluorine-modified group. This study provides an effective gene delivery system for non-small-cell lung cancer treatment.

PEG-grafted arsenic trioxide-loaded mesoporous silica nanoparticles endowed with pH-triggered delivery for liver cancer therapy.

Liver cancer (LC), one of the most common malignant primary tumors, presents a poor prognosis, high morbidity rate, and poor clinical outcomes. Despite conventional treatments have been applied prior to the deterioration, their clinical benefits were still limited. Arsenic trioxide (ATO), a toxic Chinese medicine, has been proven to efficiently inhibit the growth of LC both in vitro and in vivo. However, its therapeutic effects are hindered by poor pharmacokinetics and dose-limited toxicity. In this study, we developed a pH-responsive nanoplatform (PEG-MSN@ATO) consisting of mesoporous silica nanoparticles (MSN) that were modified with amino groups, loaded with ATO, and grafted with PEG to achieve the pH-triggered release and regulate CD8+ T cells and Treg cells in the tumor microenvironment (TME). PEG-MSN@ATO were characterized by uniform size, good loading efficiency, pH-responsive release features, decreased macrophage uptake, and enhanced dendritic cell activation in vitro. Furthermore, in vivo studies demonstrated that PEG-MSN@ATO enhanced the antitumor efficacy by inducing apoptosis and ROS production, inhibiting tumor cell proliferation and metastasis, and activating antitumor immunity within the TME. PEG-MSN@ATO also reduced the system toxicity of ATO by controlling the pH-trigger release in the tumor site. These results indicate that the PEG-MSN@ATO represents a promising drug delivery platform for reducing toxicity and enhancing the therapeutic efficacy of ATO against LC.

Graphdiyne-loaded polycaprolactone nanofiber scaffold for peripheral nerve regeneration.

Graphdiyne (GDY) is a kind of nanomaterial from the graphene carbon family with excellent physical and chemical properties. Despite some applications in medical engineering, GDY has not been used as an electroactive scaffold for tissue regeneration because of its unclear in vitro and in vivo biosafety profiles. Here, a conductive GDY nanomaterial-loaded polycaprolactone (PCL) scaffold was prepared by electrospinning technique. For the first time, the biocompatibility of GDY-based scaffold was assessed at the cellular and animal levels in a peripheral nerve injury (PNI) model. The findings indicated that the conductive three-dimensional (3D) GDY/PCL nerve guide conduits (NGCs) could significantly improve the proliferation, adhesion and glial expression of Schwann cells (SCs). The conduits were implanted into a rat 10-mm sciatic nerve defect model for 3 months in vivo. The toxicity of scaffolds to the organs was negligible, while the GDY/PCL NGCs significantly promoted myelination and axonal growth by upregulating the expression levels of SC marker (S100 ß protein), Myelin basic protein (MBP), and axon regeneration marker (ß3-tubulin protein (Tuj1) and neurofilament protein 200 (NF200)). In addition, upregulation of vascular factor expression in GDY/PCL NGC group suggested the potential role in angiogenesis to improve nerve repair by GDY nanomaterials. Our findings provide new perspectives on biocompatibility and effectiveness of GDY nanomaterial scaffold in peripheral nerve regeneration for preclinical application.

In situ forming ROS-scavenging hybrid hydrogel loaded with polydopamine-modified fullerene nanocomposites for promoting skin wound healing.

BACKGROUND: Excessive oxidative stress at the wound sites always leads to a prolonged healing and even causes chronic inflammatory wounds. Therefore, antioxidative dressings with multiple features are desired to improve wound healing performance. Herein, we fabricated a ROS-scavenging hybrid hydrogel by incorporating mussel-inspired fullerene nanocomposites (C60@PDA) into gelatin methacryloyl (GelMA) hydrogel. RESULTS: The developed C60@PDA/GelMA hydrogel showed a sustainable free radical scavenging ability, and eliminated ROS to protect cells against external oxidative stress damage. Besides, the hydrogel presented favorable cytocompatibility, hemocompatibility, and antibacterial ability in vitro. Furthermore, in a mouse full-thickness wound defect model, the in situ forming hybrid hydrogel accelerated wound closure by 38.5% and 42.9% on day 3 and day 7 over the control. Histological results demonstrated that hybrid hydrogels effectively enhanced wound healing on re-epithelialization, collagen deposition and angiogenesis. CONCLUSION: Collectively, the C60@PDA/GelMA hydrogel could be a promising dressing for promoting cutaneous wound repair.

Graphdiyne-Related Materials in Biomedical Applications and Their Potential in Peripheral Nerve Tissue Engineering.

Graphdiyne (GDY) is a new member of the family of carbon-based nanomaterials with hybridized carbon atoms of sp and sp2, including α, ß, γ, and (6,6,12)-GDY, which differ in their percentage of acetylene bonds. The unique structure of GDY provides many attractive features, such as uniformly distributed pores, highly π-conjugated structure, high thermal stability, low toxicity, biodegradability, large specific surface area, tunable electrical conductivity, and remarkable thermal conductivity. Therefore, GDY is widely used in energy storage, catalysis, and energy fields, in addition to biomedical fields, such as biosensing, cancer therapy, drug delivery, radiation protection, and tissue engineering. In this review, we first discuss the synthesis of GDY with different shapes, including nanotubes, nanowires, nanowalls, and nanosheets. Second, we present the research progress in the biomedical field in recent years, along with the biodegradability and biocompatibility of GDY based on the existing literature. Subsequently, we present recent research results on the use of nanomaterials in peripheral nerve regeneration (PNR). Based on the wide application of nanomaterials in PNR and the remarkable properties of GDY, we predict the prospects and current challenges of GDY-based materials for PNR.

Reliable Diagnostic Tests and Thresholds for Preoperative Diagnosis of Non-Inflammatory Arthritis Periprosthetic Joint Infection: A Meta-analysis and Systematic Review.

OBJECTIVE: The current diagnostic criteria for periprosthetic joint infection (PJI) are diverse and controversial, leading to delayed diagnosis. This study aimed to evaluate and unify their diagnostic accuracy and the threshold selection of serum and synovial routine tests for PJI at an early stage. METHODS: We searched the MEDLINE and Embase databases for retrospective or prospective studies which reported preoperative-available assays (serum, synovial, or culture tests) for the diagnosis of chronic PJI among inflammatory arthritis (IA) or non-IA populations from January 1, 2000 to June 30, 2022. Threshold effective analysis was performed on synovial polymorphonuclear neutrophils (PMN%), synovial white blood cell (WBC), serum C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) to find the relevant cut-offs. RESULTS: Two hundred and sixteen studies and information from 45,316 individuals were included in the final analysis. Synovial laboratory-based α-defensin and calprotectin had the best comprehensive sensitivity (0.91 [0.86-0.94], 0.95 [0.88-0.98]) and specificity (0.96 [0.94-0.97], 0.95 [0.89-0.98]) values. According to the threshold effect analysis, the recommended cut-offs are 70% (sensitivity 0.89 [0.85-0.92], specificity 0.90 [0.87-0.93]), 4100/µL (sensitivity 0.90 [0.87-0.93], specificity 0.97 [0.93-0.98]), 13.5 mg/L (sensitivity 0.84 [0.78-0.89], specificity 0.83 [0.73-0.89]), and 30 mm/h (sensitivity 0.79 [0.74-0.83], specificity 0.78 [0.72-0.83]) for synovial PMN%, synovial WBC, serum CRP, and ESR, respectively, and tests seem to be more reliable among non-IA patients. CONCLUSIONS: The laboratory-based synovial α-defensin and synovial calprotectin are the two best independent preoperative diagnostic tests for PJI. A cut off of 70% for synovial PMN% and tighter cut-offs for synovial WBC and serum CRP could have a better diagnostic accuracy for non-IA patients with chronic PJI.

Graphene Family Nanomaterials for Stem Cell Neurogenic Differentiation and Peripheral Nerve Regeneration.

Stem cells play a critical role in peripheral nerve regeneration. Nerve scaffolds fabricated by specific materials can help induce the neurogenic differentiation of stem cells. Therefore, it is a potential strategy to enhance therapeutic efficiency. Graphene family nanomaterials are widely applied in repairing peripheral nerves. However, the mechanism underlying the pro-regeneration effects remains elusive. In this review, we first discuss the properties of graphene family nanomaterials, including monolayer and multilayer graphene, few-layer graphene, graphene oxide, reduced graphene oxide, and graphene quantum dots. We also introduce their applications in regulating stem cell differentiation. Then, we review the potential mechanisms of the neurogenic differentiation of stem cells facilitated by the materials. Finally, we discuss the existing challenges in this field to advance the development of nerve biomaterials.

Multifunctional biomimetic hydrogel based on graphene nanoparticles and sodium alginate for peripheral nerve injury therapy.

Peripheral nerve injury (PNI) caused by injury may influence the patients' lifelong mobility unless there is an appropriate treatment. Tissue engineering has become a hot field to replace traditional autologous nerve transplantation due to its low surgical damage and easy-to-industrial advantages. Graphene (GR) is a kind of carbon nanomaterial with good electrical and mechanical properties that satisfy the demand for a good tissue scaffold for nerve regeneration. Herein, a novel and biosafe hydrogel is fabricated by using graphene and sodium alginate (GR-SA) together. This hydrogel not only can mimic the nerve growth microenvironment but also can promote the expression of neurotrophic substances and growth factors. Additionally, GR-SA hydrogel can significantly reduce inflammatory factors. Moreover, the results of both in vitro and in vivo tests demonstrate that GR-SA hydrogel has a promising prospect in PNI regeneration.

Blood cell-based drug delivery systems: A biomimetic platform for antibacterial therapy.

With the rapid increase in multidrug-resistance against antibiotics, higher doses of antibiotics or more effective antibiotics are needed to treat diseases, which ultimately leads to a decrease in the body's immunity and seriously threatens human health worldwide. The efficiency of antibiotics has been a large challenge for years. To overcome this problem, many carriers are utilized for anti-bacteria, attempting to optimize the delivery of such drugs and transport them safely and directly to the site of disease. Blood cell-based drug delivery systems present several advantages as compared to polymeric delivery system. These blood cells including red blood cells (RBCs), leukocytes, platelets. The blood cells and their membranes can both be used as drug carriers to deliver antibacterial drugs. In addition, blood cells can overcome many physiological/pathological obstacles faced by nanoparticles in vivo and effectively deliver drugs to the site of the disease. In this paper, we review studies on blood cell-based delivery systems used in antibacterial therapy, and analyze different roles in antibacterial therapy, which provide basis for further study in this field.

Felodipine enhances aminoglycosides efficacy against implant infections caused by methicillin-resistant Staphylococcus aureus, persisters and biofilms.

Methicillin-resistant Staphylococcus aureus (MRSA), biofilms, and persisters are three major factors leading to recurrent and recalcitrant implant infections. Although antibiotics are still the primary treatment for chronic implant infections in clinical, only few drugs are effective in clearing persisters and formed biofilms. Here, felodipine, a dihydropyridine calcium channel blocker, was reported for the first time to have antibacterial effects against MRSA, biofilm, and persisters. Even after continuous exposure to sub-lethal concentrations of felodipine, bacteria are less likely to develop resistance. Besides, low doses of felodipine enhances the antibacterial activity of gentamicin by inhibiting the expression of protein associated with aminoglycoside resistance (aacA-aphD). Next, biofilm eradication test and persisters killing assay suggested felodipine has an excellent bactericidal effect against formed biofilms and persisters. Furthermore, the result of protein profiling, and quantitative metabonomics analysis indicated felodipine reduce MRSA virulence (agrABC), biofilm formation and TCA cycle. Then, molecular docking showed felodipine inhibit the growth of persisters by binding to the H pocket of ClpP protease, which could lead to substantial protein degradation. Furthermore, murine infection models suggested felodipine in combination with gentamicin alleviate bacterial burden and inflammatory response. In conclusion, low dose of felodipine might be a promising agent for biomaterial delivery to enhance aminoglycosides efficacy against implant infections caused by MRSA, biofilm, and persisters.

Multi-Mode Antibacterial Strategies Enabled by Gene-Transfection and Immunomodulatory Nanoparticles in 3D-Printed Scaffolds for Synergistic Exogenous and Endogenous Treatment of Infections.

As research on refractory Staphylococcus aureus-related implant infection intensifies, certain challenges remain, including low antibiotic concentrations within infected areas, immune escape achieved by intracellular bacteria, myeloid-derived suppressor cells (MDSCs) inducing regional immunosuppression, and recurrence of residual pathogenic bacteria after drug suspension. Herein, a novel antimicrobial system to simultaneously address these issues is proposed. Specifically, an oxygen-species-responsive 3D-printed scaffold with shell-core nanoparticles is designed, which are loaded with an antimicrobial peptide plasmid (LL37 plasmid) and have LL37 grafted on their surface (LL37@ZIF8-LL37). The surface-grafted LL37 directly kills S. aureus and, following entry into cells, the nanoparticles kill intracellular bacteria. Moreover, in vitro and in vivo, following translation of the LL37 plasmid, cells function as factories of the antimicrobial peptide, thereby generating a continuous, prolonged antibacterial effect at the site of infection. This system significantly reduces the abnormal increase in MDSCs within the infected microenvironment, thus relieving the immunosuppressive state and restoring a protective antimicrobial immune response. Hence, this proposed antimicrobial system provides an antimicrobial immune response and a novel strategy for S. aureus-related infections by offering a combined active antimicrobial and immunotherapeutic strategy, thereby significantly reducing the recurrence rate following recovery from implant-associated infections.