Allergic rhinitis (AR) is a chronic nasal disease primarily mediated by immunoglobulin E (IgE). This condition significantly impairs patients' quality of life. Current treatments have limited clinical effectiveness. Although TH2 lymphocytes are well established as key regulators in AR pathogenesis, recent evidence underscores the pivotal role of M2 macrophages, particularly the M2a subtype, in exacerbating type 2 inflammation through recruitment of TH2 cells. To address this, 2-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) is developed, a positively charged macromolecular polysaccharide that is water-soluble and has good biocompatibility. In vitro experiments demonstrate its ability to reprogram M2a macrophages into the M1 phenotype and suppress their release of chemotactic factors. In vivo studies further confirm that HACC effectively alleviated AR symptoms in a mouse model, significantly reducing inflammatory cell infiltration in the nasal mucosa, and partially reversed the TH1-TH2 imbalance in a mouse model. Notably, its therapeutic efficacy is comparable to cetirizine, a clinically approved treatment for AR. This study highlights modulation of macrophage phenotypes as a promising strategy to inhibit type 2 inflammation and achieve effective management of allergic rhinitis.

The formation of Pseudomonas aeruginosa (P. aeruginosa) biofilm significantly enhances bacterial resistance to antimicrobial agents and escape from the host immune system, making the treatment of related infections considerably more challenging. As a potential approach for anti-biofilm strategies, the inhibition of lectins often relies on multivalent interactions to enhance binding affinity between the inhibitor and its target. In this study, targeting the P. aeruginosa lectin LecA, we constructed a polyethylene glycol-based multivalent galactoside, termed 4-Arm-PEG-Gal, by modifying the termini of 4-Arm-PEG with galactosides specific to LecA. The results indicate that 4-Arm-PEG-Gal significantly disrupts mature biofilm and is specifically recognized by the lectin LecA. Compared to the use of antibiotics alone, the combination of 4-Arm-PEG-Gal and TOB reduces antibiotic usage by 75% and additionally eradicates 73% of the bacteria within the biofilm. Furthermore, in a model of chronic lung infection, the combination of 4-Arm-PEG-Gal and TOB cleared all bacteria from the lungs, significantly reduced the secretion of TNF-α and IL-6 in the lungs, and effectively ameliorated lung damage caused by bacterial infection.

Diabetic wound healing remains a major clinical challenge due to a pathological microenvironment characterized by excessive reactive oxygen species (ROS) and chronic inflammation. Excessive ROS through multiple distinct pathways hinders the regeneration of granulation tissue, which is the essential scaffold for wound repair. Although catechol attracted considerable interest for antioxidant applications in biomaterials, its inherent chemical instability under physiological conditions severely limits its therapeutic potential and clinical applications. To address these critical challenges, an antioxidant 2,3-HCat-CS/STPP hydrogel has been developed via the freeze-thaw method, composed of 2,3-dihydroxybenzoic acid modification of chitosan (2,3-HCat-CS) and sodium tripolyphosphate (STPP). As an antioxidant, 2,3-HCat-CS was demonstrated both theoretically and experimentally to possess superior oxidative stability and ROS-scavenging property compared to the conventional 3,4-isomer. Exploration of the gelation mechanism revealed that 2,3-HCat-CS/STPP hydrogel is formed from electrostatic interactions, crystalline regions and hydrogen bonds. Hydrogel exhibited excellent antioxidant property and biocompatibility in vitro. In a full-thickness wound model in db/db mice, treatment with 2,3-HCat-CS/STPP hydrogel effectively reduced local ROS levels, mitigated inflammation and increased the levels of key anti-inflammatory cytokines (TGF-β1 and IL-10). This intervention effectively disrupted the detrimental inflammatory cycle characteristic of diabetic wounds, thereby fostering the process of angiogenesis and granulation regeneration. This work combines the molecular design of catechol and the fabrication process of chitosan gelation to create 2,3-HCat-CS/STPP hydrogel that promotes granulation regeneration in diabetic wounds, which presents a potential therapeutic platform for chronic wounds management.

Infections caused by anaerobic bacteria are common in oxygen-poor regions. Their slow metabolism makes most antibiotics less effective. And the small-molecule nutrients produced by anaerobic fermentation create a favorable growth environment for other bacteria, leading to multi-species infections. Due to the low tolerance of anaerobic bacteria to reactive oxygen species (ROS), stimulation of endogenous ROS generation could be a promising way to kill anaerobic bacteria. In this work, we used an antimicrobial peptide (AMP) (sequence: WRKFRRFKFRW-NH2, WRK for short) that induces anaerobic bacteria to produce intracellular ROS to treat infections caused by Propionibacterium acnes (P. acnes), a typical anaerobic bacterium that is often commensal in the skin. This antibacterial mechanism avoids the development of drug resistance and does not rely on oxygen. WRK peptide demonstrated excellent antimicrobial performance against P. acnes, inhibiting free-floating bacteria at 4 µg mL−1 and destroying biofilms at 64 µg mL−1. AMP can be delivered to the dermis through microneedles and effectively inhibits the proliferation of P. acnes in the infected area. In a mouse model of back acne, we confirmed the therapeutic effect of this AMP microneedle on P. acnes infection in vivo. The antibacterial microneedle treatment significantly reduced inflammation, demonstrating superior therapeutic efficacy compared to commercial clindamycin gel.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease, causing irreversible lung scarring and respiratory failure. CD206+ M2 macrophages play a key role in its progression. In this study, we utilize the pro-inflammatory properties of plant viruses to develop a mannose-modified tobacco mosaic virus nanoparticle (TMV-OEG8-Man), which targets and reprograms profibrotic macrophages to inhibit IPF. TMV-OEG8-Man alters the CD206+ M2 macrophage phenotype in vitro, suppressing profibrotic genes (Mrc1, Spp1, Ccr2) and signaling pathways (MAPK, TGF-beta, PI3K-Akt, mTOR, Wnt), thereby reducing the transition of fibroblasts to myofibroblasts. When administered via aerosol, TMV-OEG8-Man achieves prolonged lung retention with minimal systemic exposure. In mice with bleomycin-induced pulmonary fibrosis, a single dose during fibroproliferation attenuated fibrosis progression, increasing survival rate from 50% to 100%, and preserving lung architecture. This study establishes plant viral nanoparticles as a macrophage reprogramming strategy with therapeutic potential for organ fibrosis.

Biological nanoparticles, particularly rod-shaped plant viruses, have emerged as promising candidates for various biomedical applications. This review focuses on the morphological characteristics and modification strategies of rod-shaped plant viruses such as tobacco mosaic virus, potato virus X, and papaya mosaic virus. These viruses offer versatile modification approaches, including chemical, genetic, and bio-modifications, as well as aspect ratio regulation. Their applications in drug delivery, antibacterial treatments, RNA delivery, bioimaging, and immune modulation are extensively discussed. Rod-shaped plant viruses exhibit unique advantages, such as uniformity in size and molecular weight, excellent biocompatibility, diverse modifiability and inherent immunogenicity, making them highly suitable for biomedical applications. However, challenges remain in their clinical translation. This review aims to provide insights into the potential of rod-shaped plant viruses as biological nanoparticles and stimulate further research in the field of virus-based biomaterials, which may lead to innovative solutions in drug delivery, immune-related therapies and vaccine development.

This study investigates a novel pH-responsive hydrogel composed of polyvinyl alcohol (PVA) and boric acid (BA) designed for the controlled release of salvianolic acid B (SAB), addressing the critical challenge of scar formation and skin regeneration. The dual-crosslinked network architecture of the hydrogel exhibits remarkable pH sensitivity, enabling it to achieve a peak SAB release within 48 hours in the acidic microenvironment characteristic of early-stage wound healing. In vitro assessments demonstrated that the PVA-BA-SAB hydrogel significantly inhibits fibroblast activation and mitigates abnormal collagen deposition, effectively preventing excessive scar formation. Transcriptome sequencing reveals the potential role of PVA-BA-SAB hydrogel in balancing TGF-β and Wnt signaling pathways. Furthermore, in vivo studies revealed enhanced tissue regeneration, characterized by improved collagen organization and increased vascularization, as well as the promotion of mature hair follicle development. The hydrogel’s biocompatibility, mechanical robustness and adhesive properties were also thoroughly evaluated, confirming its suitability for clinical applications. These findings suggest that the PVA-BA-SAB hydrogel fully exerts the excellent characteristics of biomaterials and maximizes the pharmacological effect of SAB. Our innovative drug delivery system not only facilitates enhanced wound healing but also offers a strategic approach to minimize scarring. This research provides valuable insights into innovative therapeutic strategies for effective wound management and tissue repair.

Biofilm formation is one of the key reasons that bacterial infections are difficult to treat. So it is of great significance to develop effective strategies to resist bacterial biofilms. Although antibiotics are important clinical tools for the treatment of bacterial infections, their therapeutic efficacy is often unsatisfactory when targeting bacterial biofilm-associated diseases. In this study, exopolysaccharides (EPS) from Escherichia coli (E. coli) were extracted and purified. It was demonstrated that the obtained E. coli EPS had the ability to inhibit methicillin-resistant Staphylococcus aureus (MRSA) biofilm formation and disperse a mature biofilm. To improve the anti-biofilm effect of vancomycin (VAN), E. coli EPS was used in combination with VAN. The combination increased the inhibition rate of MRSA biofilm and increased the dispersion rate of mature biofilm from 10% to 80%. When combined with E. coli EPS, the number of bacterial colonies within the MRSA biofilm remarkably decreased by 88%, resulting in a significant improvement over the use of VAN alone at an equivalent concentration. Meanwhile, E. coli EPS could down-regulate the expression of MRSA biofilm-related genes. E. coli EPS showed good anti-biofilm effect, and E. coli EPS/VAN combination could provided a potential strategy for treatment of MRSA biofilm infections.

Advanced Healthcare MaterialsVolume 13, Issue 17 2470109 Inside Front CoverFree Access Histatin 5-Inspired Short-Chain Peptides Selectively Combating Pathogenic Fungi with Multifaceted Mechanisms (Adv. Healthcare Mater. 17/2024) Guojun Lu, Guojun LuSearch for more papers by this authorXiaoyan Ju, Xiaoyan JuSearch for more papers by this authorMeng Zhu, Meng ZhuSearch for more papers by this authorJinzhao Ou, Jinzhao OuSearch for more papers by this authorDandan Xu, Dandan XuSearch for more papers by this authorKejia Li, Kejia LiSearch for more papers by this authorWei Jiang, Wei JiangSearch for more papers by this authorChenxiao Wan, Chenxiao WanSearch for more papers by this authorYe Tian, Ye TianSearch for more papers by this authorZhongwei Niu, Zhongwei NiuSearch for more papers by this author Guojun Lu, Guojun LuSearch for more papers by this authorXiaoyan Ju, Xiaoyan JuSearch for more papers by this authorMeng Zhu, Meng ZhuSearch for more papers by this authorJinzhao Ou, Jinzhao OuSearch for more papers by this authorDandan Xu, Dandan XuSearch for more papers by this authorKejia Li, Kejia LiSearch for more papers by this authorWei Jiang, Wei JiangSearch for more papers by this authorChenxiao Wan, Chenxiao WanSearch for more papers by this authorYe Tian, Ye TianSearch for more papers by this authorZhongwei Niu, Zhongwei NiuSearch for more papers by this author First published: 05 July 2024 https://doi.org/10.1002/adhm.202470109AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Selectively Combating Fungi The peptide WHI selectively combats fungi without destroying commensal bacteria. When WHI meets the cell membrane, it changes from the PPII conformation to α-helix conformation and targets the nucleus and mitochondria, leading to fungal death. More details can be found in article 2303755 by Zhongwei Niu and co-workers. Volume13, Issue17July 5, 20242470109 RelatedInformation

Pseudomonas aeruginosa (P. aeruginosa) is a major pathogen that causes infectious diseases. It has high tendency to form biofilms, resulting in the failure of traditional antibiotic therapies. Inspired by the phenomenon that co-culture of Escherichia coli (E. coli) and P. aeruginosa leads to a biofilm reduction, we reveal that E. coli exopolysaccharides (EPS) can disrupt P. aeruginosa biofilm and increase its antibiotic susceptibility. The results show that E. coli EPS effectively inhibit biofilm formation and disrupt mature biofilms in P. aeruginosa, Staphylococcus aureus, and E. coli itself. The maximal inhibition and disruption rates against P. aeruginosa biofilm are 40% and 47%, respectively. Based on the biofilm-disrupting ability of E. coli EPS, we develop an E. coli EPS/antibiotic combining strategy for the treatment of P. aeruginosa biofilms. The combination with E. coli EPS increases the antibacterial efficiency of tobramycin against P. aeruginosa biofilms in vitro and in vivo. This study provides a promising strategy for treating biofilm infections. Statement of Significance Biofilm formation is a leading cause of chronic infections. It blocks antibiotics, increases antibiotic-tolerance, and aids in immune evasion, thus representing a great challenge in clinic. This study proposes a promising approach to combat pathogenic Pseudomonas aeruginosa (P. aeruginosa) biofilms by combining Escherichia coli exopolysaccharides with antibiotics. This strategy shows high efficiency in different P. aeruginosa stains, including two laboratory strains, PAO1 and ATCC 10145, as well as a clinically acquired carbapenem-resistant strain. In addition, in vivo experiments have shown that this approach is effective against implanted P. aeruginosa biofilms and can prevent systemic inflammation in mice. This strategy offers new possibilities to address the clinical failure of conventional antibiotic therapies for microbial biofilms.

Short-chain antifungal peptides (AFPs) inspired by histatin 5 have been designed to address the problem of antifungal drug resistance. These AFPs demonstrate remarkable antifungal activity, with a minimal inhibitory concentration as low as 2 µg mL-1. Notably, these AFPs display a strong preference for targeting fungi rather than bacteria and mammalian cells. This is achieved by binding the histidine-rich domains of the AFPs to the Ssa1/2 proteins in the fungal cell wall, as well as the reduced membrane-disrupting activity due to their low amphiphilicity. These peptides disrupt the nucleus and mitochondria once inside the cells, leading to reactive oxygen species production and cell damage. In a mouse model of vulvovaginal candidiasis, the AFPs demonstrate not only antifungal activity, but also promote the growth of beneficial Lactobacillus spp. This research provides valuable insights for the development of fungus-specific AFPs and offers a promising strategy for the treatment of fungal infectious diseases.

Macrophage polarization and phenotypic switching have a significant impact on the immune microenvironment of wounds, making them crucial for wound healing. Creating immune-adapted microenvironment throughout the wound repair process by regulating macrophage polarization supports rapid wound healing. We explored the segmented use of M1-polarizing and M2-polarizing materials at different healing stages and found that this combination can significantly shorten the healing time. The macrophage polarization could be adjusted to M1 phenotype and M2 phenotype by selective modification of chitosan with dicyandiamide or polyethylene glycol, respectively. In a rat full-thickness infected wound model, combining dicyandiamide modified chitosan (DICY-CS) for M1 macrophage polarization in the inflammatory phase and PEGylated chitosan (PEG-CS) for M2 macrophage polarization in the proliferative phase significantly reduced wound healing time. A higher degree of re-epithelialization, collagen deposition and neovascularization were observed in wounds treated with this combination approach compared to the antimicrobial agents Silvadene and DICY-CS or PEG-CS alone. The use of different macrophage polarizing materials separately in different healing stages provided an optimal immune microenvironment and accelerated wound healing. This strategy provides a more comprehensive understanding of the wound healing process. It will be a new insight for the treatment of more complex and difficult-to-heal wounds such as pressure ulcers and diabetic wounds.

Peptide vaccines induce specific neutralizing antibodies and are effective in disease prevention and treatment. However, peptide antigens have a low immunogenicity and are unstable, requiring efficient vaccine carriers to enhance their immunogenicity. Here, we develop a tobacco mosaic virus (TMV)-based peptide vaccine for transdermal immunization using a tip-loaded dissolving microneedle (MN) patch. TMV is decorated with the model peptide antigen PEP3. The prepared TMV-PEP3 promotes dendritic cell maturation and induces dendritic cells to overexpress MHC II, costimulatory factors, and pro-inflammatory factors. By encapsulation of TMV-PEP3 in the tips of a trehalose MN, TMV-PEP3 can be delivered by MN and significantly promote local immune cell infiltration. In vivo studies show that both subcutaneous injection and MN administration of TMV-PEP3 increase the production of anti-PEP3 IgG antibodies and the harvested serum can induce complement-dependent cytotoxicity. This work provides a promising strategy for constructing efficient and health-care-friendly peptide vaccines.

Oxidative stress caused by excessive reactive oxygen species (ROS) accumulation significantly hinders wound healing in patients with diabetes. Scavenging ROS and reducing inflammation are crucial for rapid healing. In this work, a multi-responsive sodium hyaluronate (HA)/tannic acid (TA) hydrogel was developed based on boronate ester bonds. Sodium hyaluronate with 3-aminophenyl boronic acid modification (HA-APBA) was mixed and crosslinked with TA to form HA-APBA/TA hydrogels. These hydrogels are injectable, self-healing, and biocompatible. The HA-APBA/TA hydrogels could release free TA through the collapse of the structure at low pH, high H2O2 concentration, and high glucose concentration, thus possessing good ROS scavenging ability. In full-thickness skin wounds of db/db mice, the HA-APBA/TA hydrogels promoted wound healing, collagen deposition, and significant angiogenesis. Furthermore, they have been shown to effectively reduce the levels of inflammatory factors in wounds and lower the expression of CD86, a pro-inflammatory macrophage surface marker. This resulted in a more effective transition of wound healing from the inflammatory phase to the proliferative phase. This study provides an optional strategy for alleviating oxidative stress and controlling excessive inflammation, thereby promoting diabetic wound healing.

Fungal infections are becoming an increasingly serious challenge in clinic due to the increase in drug resistance and the lack of anti-fungal drugs. Vaccination is a useful approach to prevent fungal infections. However, the balance between effectiveness and side effects presents a challenge in vaccine development. In this work, we designed a plant virus-based conjugate vaccine. The non-infectiveness and innate immunogenicity of plant viruses make this vaccine both safe and effective. By conjugating a fungal antigenic peptide to the tobacco mosaic virus (TMV), the resultant vaccine improved the uptake efficiency of antigenic peptides by antigen-presenting cells and enhanced the ability to target lymph nodes. The results of in vivo vaccination in mice showed a significant increase of antigen-specific IgG antibody levels induced by the TMV conjugate vaccine. This work suggests that TMV conjugate vaccines may become a potential vaccine candidate for preventing fungal infections.

Osteomyelitis caused by methicillin-resistant Staphylococcus aureus (MRSA) is a challenging and life-threatening disease due to its long duration and deep site of occurrence. Herein, we design an in situ formed antibacterial hydrogel with collagenase-respontive activity for the prevention of MRSA-induced osteomyelitis. This hydrogel is constructed by chemical bonding between a 4-arm polyethylene glycol maleimide (4-Arm-PEG-Mal), an N-terminal maleimidated antimicrobial peptide (Mal-AMP) and a collagenase-cleavable peptide with two thiol groups (HS-VPM-SH). Collagenase-induced hydrogel cleavage confers on-demand delivery of the antimicrobial peptide, thereby enhancing the combating activity against MRSA in an infected environment. The designed hydrogel, namely AMP/VPM/PEG hydrogel, can be formed rapidly in situ under physiological conditions due to the rapid bonding between the maleimide and thiol groups. In the in vivo rat osteomyelitis model, the AMP/VPM/PEG hydrogel can be administered by simply injecting the 4-Arm-PEG-Mal and peptide solutions with a 26G needle, which is a minimally invasive method. In vivo evaluation further demonstrates that AMP/VPM/PEG hydrogel can successfully prevent MRSA-induced osteomyelitis. This work provides a minimally invasive approach for intramedullary delivery of antimicrobial peptides on-demand and may provide a viable strategy for the osteomyelitis prevention in clinic.

Fungal keratitis (FK) is a leading cause of preventable blindness and eye loss. The poor antifungal activity, increased drug resistance, limited corneal permeability, and unsatisfactory biosafety of conventional antifungal eye drops are among the majority of the challenges that need to be addressed for currently available antifungal drugs. Herein, this study proposes an effective strategy that employs chitosan-poly(ethylene glycol)-LK13 peptide conjugate (CPL) in the treatment of FK. Nanoassembly CPL can permeate the lipophilic corneal epithelium in the transcellular route, and its hydrophilicity surface is a feature to drive its permeability through hydrophilic stroma. When encountering fungal cell membrane, CPL dissembles and exposes the antimicrobial peptide (LK13) to destroy fungal cell membranes, the minimum inhibitory concentration values of CPL against Fusarium solani (F. solani) are always not to exceed 8 μg peptide/mL before and after drug resistance induction. In a rat model of Fusarium keratitis, CPL demonstrates superior therapeutic efficacy than commercially available natamycin ophthalmic suspension. This study provides more theoretical and experimental supports for the application of CPL in the treatment of FK.

The phenotype of tumor-associated macrophages plays an important role in their function of regulating the tumor immune microenvironment. The M1-phenotype macrophages display tumor-killing and immune activating functions. Here we show that the tobacco mosaic virus (TMV), a rod-like plant virus, can polarize macrophages to an M1 phenotype and shape a tumor-suppressive microenvironment. RAW 264.7 cells and bone marrow derived-macrophages (BMDMs) can recognize TMV via Toll-like receptor-4, and then the MAPK and NF-κB signaling pathways are activated, leading to the production of pro-inflammatory factors. Furthermore, the in vivo assessments on a subcutaneous co-injection tumor model show that the TMV-polarized BMDMs shape a tumor-suppressive microenvironment, resulting in remarkable delay of 4T1 tumor growth. Another in vivo assessment on an established tumor model indicates the high tumor-metastasis-inhibiting capacity of TMV-polarized BMDMs. This work suggests a role for this plant virus in macrophage-mediated therapeutic approaches and provides a strategy for tumor immunotherapy.

Surface-associated microbe contamination by Gram-negative bacteria poses a serious problem in medical care. Cationic peptides or polymers are the main materials used for antibacterial surface coating, but the positive charge may lead to blood coagulation. Therefore, exploiting surface coating which is free of positive charge and is effective for Gram-negative bacteria inactivation is in urgent need. In this study, inspired by the affinity between lipopolysaccharides of Gram-negative bacteria and Toll-like receptors of immune cells, we develop a leucine-based tetrapeptide coating strategy for combating Gram-negative bacteria. The obtained surface has excellent bactericidal activity against Gram-negative bacteria like Pseudomonas aeruginosa and Escherichia coli. A 1 mm2 coated glass surface could kill > 9.9 × 104 CFU bacteria in 1 h and has nearly no damage to mammal cells. Moreover, this surface coating strategy could be applied on various surfaces like glass slices, glass capillary cavity and thermoplastic polyurethane slices. And the coated surface could largely mitigate the microbe contamination in an in vivo subcutaneous implantation. This work paves a new way for antibacterial surface-coating which is behaving no positive charge and is of great importance for biomedical devices.