Abstract Bacterial infection and impaired angiogenesis make the treatment of diabetic foot ulcers (DFU) extremely challenging. Cationic polymers are expected to treat infected wounds due to their excellent antibacterial properties, but still, it is difficult to meet the therapeutic needs of pro‐angiogenesis and anti‐infections due to their simple construction units and outmoded synthesis methods. Herein, a cationic poly(pentahydropyrimidine) (PPHP) library with strong modifiability is synthesized to construct a hybrid hydrogel with synergistic therapeutic effects for the treatment of infected DFUs. It is found that the as‐synthesized hybrid hydrogel can up‐regulate angiogenesis‐related gene (HIF‐1, VEGF, and bFGFR/bFGF) expression and targeted disruption of bacterial cell membranes, which finally promotes the healing of infected DFU (wound healing rate: 92%) within 10 days. This hydrogel, thus, holds great promise in developing new strategies to significantly enhance the treatment of DFU and other bacterial‐infected pathological diagnoses. 

Poly(pentahydropyrimidine)‐Based Hybrid Hydrogel with Synergistic Antibacterial and Pro‐Angiogenic Ability for the Therapy of Diabetic Foot Ulcers

In the last few decades, we have witnessed the great advances of molecular self-assembly in biomedical applications. Among the building blocks for molecular self-assembly, peptide exhibits several merits such as structural designability, feasible synthetic methodology, and robust self-assembling tendency. Particularly, the excellent biocompatibility, biodegradability and bioactivity bestow peptide-based assemblies with dominant advantages as biological materials. Herein, the state-of-the-art research on peptide self-assembly is reviewed. First, we discuss the representative achievements of ex situ peptide self-assembly for cargo delivery carriers, self-deliverable nanomedicines, and tissue engineering materials, which are contributed to the prefabrication of micro/nanoarchitectures in solution. After that, the in vitro/in vivo formation of peptide-based nanomaterials is presented, which is nominated as in situ peptide self-assembly. The design principle and trigger module of in situ peptide self-assembly are summarized, with an emphasis on its biological effects used for disease imaging and therapy. Finally, the combinational modality, i.e. integrating ex situ construction of peptide self-assemblies for their delivery with in situ adaptive transformation of their morphologies to optimize outcomes, is attached, which bridges the gap between ex situ and in situ peptide self-assembly. We hope this review will provide a panoramic sketch of peptide self-assembly, which is helpful for chemists and material scientists to exploit more biomedical functions from peptide libraries for disease treatments. 

A comprehensive review on peptide-bearing biomaterials: From ex situ to in situ self-assembly

Living organisms fabricate biomacromolecules such as DNA, RNA, and proteins by the self-assembly process. The research on the mechanism of biomacromolecule formation also inspires the exploration of in vivo synthesized biomaterials. By elaborate design, artificial building blocks or precursors can self-assemble or polymerize into functional biomaterials within living organisms. In recent decades, these so-called in vivo synthesized biomaterials have achieved extensive applications in cell-fate manipulation, disease theranostics, bioanalysis, cellular surface engineering, and tissue regeneration. In this review, we classify strategies for in vivo synthesis into non-covalent, covalent, and genetic types. The development of these approaches is based on the chemical principles of supramolecular chemistry and synthetic chemistry, biological cues such as enzymes and microenvironments, and the means of synthetic biology. By summarizing the design principles in detail, some insights into the challenges and opportunities in this field are provided to enlighten further research. 

Synthesizing biomaterials in living organisms.

Oral diseases are prevalent but challenging diseases owing to the highly movable and wet, microbial and inflammatory environment. Polymeric materials are regarded as one of the most promising biomaterials due to their good compatibility, facile preparation, and flexible design to obtain multifunctionality. Therefore, a variety of strategies have been employed to develop materials with improved therapeutic efficacy by overcoming physicobiological barriers in oral diseases. In this review, we summarize the design strategies of polymeric biomaterials for the treatment of oral diseases. First, we present the unique oral environment including highly movable and wet, microbial and inflammatory environment, which hinders the effective treatment of oral diseases. Second, a series of strategies for designing polymeric materials towards such a unique oral environment are highlighted. For example, multifunctional polymeric materials are armed with wet-adhesive, antimicrobial, and anti-inflammatory functions through advanced chemistry and nanotechnology to effectively treat oral diseases. These are achieved by designing wet-adhesive polymers modified with hydroxy, amine, quinone, and aldehyde groups to provide strong wet-adhesion through hydrogen and covalent bonding, and electrostatic and hydrophobic interactions, by developing antimicrobial polymers including cationic polymers, antimicrobial peptides, and antibiotic-conjugated polymers, and by synthesizing anti-inflammatory polymers with phenolic hydroxy and cysteine groups that function as immunomodulators and electron donors to reactive oxygen species to reduce inflammation. Third, various delivery systems with strong wet-adhesion and enhanced mucosa and biofilm penetration capabilities, such as nanoparticles, hydrogels, patches, and microneedles, are constructed for delivery of antibiotics, immunomodulators, and antioxidants to achieve therapeutic efficacy. Finally, we provide insights into challenges and future development of polymeric materials for oral diseases with promise for clinical translation.

Emerging polymeric materials for treatment of oral diseases: design strategy towards a unique oral environment.

Abstract Diabetic wounds tend to develop into nonhealing wounds associated with the complex inflammatory microenvironment of uncontrollable bacterial infection, reactive oxygen species (ROS) accumulation, and chronic hypoxia. Damaged blood vessels hinder metabolic circulation, aggravating hypoxia, and ROS accumulation and further exacerbating the diabetic wound microenvironment. However, existing treatments with a single functionality have difficulty healing complicated diabetic wounds. Therefore, developing an integrative strategy to improve the hostility of the diabetic wound microenvironment is urgently needed. Herein, multifunctional genipin (GP)‐crosslinked chitosan (CS)‐based hydrogels decorated with the biomimetic metal–organic framework (MOF)‐nanozymes and the natural antibacterial agent chlorogenic acid (CGA), which is named MOF/CGA@GP‐CS (MCGC), are prepared. With catalase (CAT)‐like activity, these dual‐metal MOF‐nanozymes are promising bioreactors for simultaneously alleviating ROS accumulation and hypoxia by converting elevated endogenous H 2 O 2 into dissolved oxygen in diabetic wounds. In addition, the other component of natural polyphenolic CGA acts as a mild antibacterial agent, efficiently inhibiting wound infection and avoiding antibiotic resistance. Impressively, the MCGC hydrogels accelerate infected diabetic wound healing by eliminating oxidative stress, increasing oxygenation, and reversing bacterial infection in vivo. In this work, an effective strategy based on multifunctional hydrogel wound dressings is successfully developed and applied in diabetic wound management. 

Kill Two Birds with One Stone: Dual‐Metal MOF‐Nanozyme‐Decorated Hydrogels with ROS‐Scavenging, Oxygen‐Generating, and Antibacterial Abilities for Accelerating Infected Diabetic Wound Healing

Antimicrobial peptides (AMPs) with dual intrinsic antibacterial and antioxidative functions have emerged as promising choice to cure infected wound. However, the most widely applied approach to endow AMPs with antioxidative function is to combine with antioxidative moieties, which may affect the spatial structure and physiological stability of AMPs. Herein, a new type of AMPs with inherent desired stability, antibacterial activity, and reactive oxygen species (ROS) scavenging is developed to effectively heal the infected wound. This formulation is in situ formed at wound site by tyrosinase‐triggered oxidation and self‐assembly of lyophilized antimicrobial peptide Trp‐Arg‐Trp‐Arg‐Trp‐Tyr, providing enhanced stability and a fourfold and sevenfold increasement in antibacterial efficiency against E. coli and S. aureus compared to peptide monomers. The antimicrobial peptide is first oxidized and then assembled into nanoparticles. The melanin‐like structure has been demonstrated with efficient antioxidant properties, and the experimental data show that peptide nanoparticles to scavenge superoxide radicals, hydroxyl radicals, and H2O2. In vivo experiments confirmed that peptide nanoparticles effectively heal infected wounds and obviously reduce ROS. Overall, the research provides a new approach to formulating antimicrobial peptides to treat wound with high healing efficiency.

In Situ Enzyme‐Induced Self‐Assembly of Antimicrobial‐Antioxidative Peptides to Promote Wound Healing

Delayed implant-associated infection is an important challenge, as the treatment involves a high risk of implant replacement. Mussel-inspired antimicrobial coatings can be applied to coat a variety of implants in a facile way, but the adhesive 3,4-dihydroxyphenylalanine (DOPA) group is prone to oxidation. Therefore, an antibacterial polypeptide copolymer poly(Phe7-stat-Lys10)-b-polyTyr3 was designed to prepare the implant coating upon tyrosinase-induced enzymatic polymerization for preventing implant-associated infections. Both poly(Phe7-stat-Lys10) and polyTyr3 blocks have specific functions: the former provides intrinsic antibacterial activity with a low risk to induce antimicrobial resistance, and the latter is attachable to the surface of implants to rapidly generate an antibacterial coating by in situ injection of polypeptide copolymer since tyrosine could be oxidized to DOPA under catalyzation of skin tyrosinase. This polypeptide coating with excellent antibacterial effect and desirable biofilm inhibition activity is promising for broad applications in a multitude of biomedical materials to combat delayed infections.

An Antibacterial Polypeptide Coating Prepared by In Situ Enzymatic Polymerization for Preventing Delayed Infection of Implants.

Uniform gold nanoclusters (AuNCs) are hardly available unless through abundant strong ligands (at the cost of low catalytic activity and narrow catalytic spectrum) or through well-defined (but expensive) templates, and it appears a tougher challenge for direct preparing supported and uniform AuNCs. Here, we show that with an amphiphilic and dendritic molecular template in hand, highly catalytically active, uniform, and supported AuNCs are one-pot achievable. Branched polyethylenimine (PEI) is modified with a few thioether groups and alkylated with hydrophobic acetyls and polystyrene chains to afford reverse micelle-like dendritic polymers. The structurally optimized dendritic polymer can act as a surfactant to mediate very stable water-in-oil high internal phase emulsion (HIPE) within a wide pH spectrum. Moreover, the dendritic polymer switches into the unimolecular state along the interface of the HIPE when pH is below 6, which is critical to the formation of uniform AuNCs. Experimentally, upon the transformation of HIPE into an open-cellular polyHIPE, the gold ions are simultaneously transformed into AuNCs. Direct preparation of the supported and uniform AuNCs (1.8 ± 0.2 nm) are feasible because the dendritic polymer can simultaneously act as a surfactant, a polymer ligand, and a unimolecular template. Meanwhile, the trace thioether groups in the PEI core reduce the size of AuNCs by enhancing nucleation of AuNCs since in the absence of thioether groups, larger particles are obtained. The supported AuNCs are catalytically active because they are stabilized by weak coligands. For the model reaction of the catalyzed reduction of 4-nitrophenol, the catalyst shows a turnover frequency of 112.5 h–1, which is very high. The catalyst is durable and well recyclable. 

Dendritic Molecular Template Mediates and Directs Self-Assembly of Uniform Gold Nanoclusters to One-Pot Afford 3D-Supported Active Catalysts

Rational Design of Polymeric mRNA Delivery Vectors to Achieve Excellent Room-Temperature Storage Stability and Delivery Efficiency

Chronic diabetic wounds remain one of the most intractable complications of diabetes, demanding therapeutic strategies that can simultaneously regulate local glucose levels, combat persistent infections, and promote angiogenesis. Here, we engineer a living-therapeutic microneedle system that integrates metabolically active probiotics with a pH-responsive carboxymethyl chitosan/l-arginine matrix to autonomously orchestrate wound microenvironment remodeling. Leveraging the unique metabolic capacity of Lactobacillus reuteri, our system rapidly and sustainably reduces local hyperglycemia (84.8% reduction over 48 h) while generating broad-spectrum antimicrobial reuterin in situ, circumventing drawbacks of conventional antibiotics. In parallel, a microneedle matrix scavenges reactive oxygen species and drives robust angiogenesis. In infected diabetic mice, a single administration can accelerate wound closure by 7.3-fold, eliminate pathogens via synergistic bactericidal and nutrient-competition mechanisms, and restore normoglycemia without rebound. This synergistic "metabolic engine-microenvironment modulation" paradigm addresses key barriers in diabetic wound healing and offers a scalable platform for living microbe-material therapeutics in chronic disease management.

Living Therapeutic Microneedles Integrated with Built-In Metabolic Engines for Autonomous Diabetic Wound Management.

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