Zinc finger-inspired peptide-metal-phenolic nanointerface enhances bone-implant integration under bacterial infection microenvironment through immune modulation and osteogenesis promotion

Orthopedic and dental implantations under bacterial infection microenvironment face significant challenges in achieving high-quality bone-implant integration. Designing implant coatings that incorporate both immune defense and anti-inflammation is difficult in conventional single-functional coatings. We introduce a multifunctional nanointerface using a zinc finger-inspired peptide-metal-phenolic nanocoating, designed to enhance implant osseointegration under such conditions. Abaloparatide (ABL), a second-generation anabolic drug for treating osteoporosis, can be integrated into the design of a zinc-phenolic network constructed on the implant surface (ABL@ZnTA). Importantly, the phenolic-coordinated Zn2+ ions in ABL@ZnTA can act as zinc finger motif to co-stabilize the configuration of ABL through multiple molecular interactions, enabling high bioactivity, high loading capacity (1.36 times), and long-term release (>7 days) of ABL. Our results showed that ABL@ZnTA can modulate macrophage polarization from the pro-inflammatory M1 towards the anti-inflammatory M2 phenotype, promoting immune osteogenesis with increased OCN, ALP, and SOD 1 expression. Furthermore, the ABL@ZnTA significantly reduces inflammatory fibrous tissue encapsulation and enhances the long-term stability of the implants, indicated by enhanced binding strength (6 times) and functional connectivity (1.5−3 times) in the rat bone defect model infected by S. aureus. Overall, our research offers a nano-enabled synergistic strategy that balances infection defense and osteogenesis promotion in orthopedic and dental implantations.

Microenvironment-responsive metal-phenolic network release platform with ROS scavenging,anti-pyroptosis,and ECM regeneration for intervertebral disc degeneration

Intervertebral disc degeneration(IVDD)can be caused by aging,injury,and genetic factors.The pathological changes associated with IVDD include the excessive accumulation of reactive oxygen species(ROS),cellular pyroptosis,and extracellular matrix(ECM)degradation.There are currently no approved specific molecular therapies for IVDD.In this study,we developed a multifunctional and microenvironment-responsive metal-phenolic network release platform,termed TMP@Alg-PBA/PVA,which could treat(IL-1β)-induced IVDD.The metal-phenolic network(TA-Mn-PVP,TMP)released from this platform targeted mitochondria to efficiently scavenge ROS and reduce ECM degradation.Pyroptosis was suppressed through the inhibition of the IL-17/ERK signaling pathway.These findings demonstrate the versatility of the platform.And in a rat model of IVDD,TMP@Alg-PBA/PVA exhibited excellent therapeutic effects by reducing the progression of the disease.TMP@Alg-PBA/PVA,therefore,presents clinical potential for the treatment of IVDD.

Tannic acid-based metal-phenolic networks as a versatile platform to mediate cell therapy

Surface modification using biomaterials is crucial for constructing bioactive interfaces that can control cell behavior,regulate biological processes,and interact with specific biomolecules.Tannic acid(TA),a naturally derived polyphenol,is of particular interest due to its ability to complex ions,facilitating the fabrication of coordination networks through self-assembly of TA and metal ions,known as metal-phenolic networks(MPNs).These MPNs can form stable,yet dynamic structures that can be further engineered or tailored for specific therapeutic needs.Synthetic TA-based MPN complexes have been constructed to modify diverse biointerfaces due to their unique physiochemical properties,including universal adhesion,pH responsiveness,controllable size and stiffness,ease of preparation,and excellent biocompatibility,which are highly advantageous for various biological applications,particularly in cell therapy.This review explores the synthesis,properties,and applications of TA-based MPNs in the context of therapeutic cells,including bacteria,yeast,and mammalian cells.Key aspects such as biocompatibility,biodegradability,the ability to modulate cellular environments,and clinical translation are discussed,highlighting the potential of TA-based MPNs to advance cell therapy.

A biologically stable, self-catalytic DNAzyme machine encapsulated by metal-phenolic nanoshells for multiple microRNA imaging

DNAzyme machines play critical roles in the fields of cell imaging, disease diagnosis, and cancer therapy. However, the applications of DNAzyme machines are limited by the nucleases-induced degradation,non-specific binding of proteins, and insufficient provision of cofactors. Herein, protected DNAzyme machines with different cofactor designs(referred to as Pro Ds) were nanoengineered by the construction of multifunctional metal-phenolic nanoshells to deactivate the interferential proteins, including nucleases and non-specific binding proteins. Moreover, the nanoshells not only facilitate the cellular internalization of Pro Ds but provide specific metal ions acting as cofactors of the designed DNAzymes. Cellular imaging results demonstrated that Pro Ds could effectively and simultaneously monitor multiple tumor-related micro RNAs in living cells. This facile and rapid strategy that encapsulates DNAzyme machines into the protective metal-phenolic nanoshells is anticipated to extend to a wide range of functional nucleic acidsbased biomedical applications.

A step-by-step multiple stimuli-responsive metal-phenolic network prodrug nanoparticles for chemotherapy

Currently,chemotherapy is the main clinical therapy of tumors.Depressingly,most chemotherapeutic drugs such as doxorubicin and paclitaxel(PTX)have poor water solubility,leading to low bioavailability and serious side effects.Till now,although a variety of nanoparticulate drug delivery systems have been designed to ameliorate the above disadvantage of chemotherapy drugs,their application is still severely limited due to the complex preparation,poor stability,low drug loading,and premature drug release.Herein,a metal phenolic network-based drug delivery system with superior stability,satisfactory drug loading capacity,good biocompatibility,reduced undesired premature release,and excellent anti-tumor ability has been established for achieving step-by-step multiple stimuli-responsive drug delivery.Firstly,the redox-responsive dimeric paclitaxel(diPTX)prodrug was synthesized.Then diPTX@Fe&tannic acid(diPTX@Fe&TA)complex nanoparticles with satisfactory PTX loading capacity were obtained by deposition of Fe&TA network complex on the nanocore of diPTX rapidly with a simple method.The diPTX@Fe&TA nanoparticles have a hydrodynamic diameter of 152.6±1.2 nm,long-term colloidal stability,and high PTX loading content of 24.7%.Besides,diPTX@Fe&TA could expose to the acidic lysosomal environment and the reduction cytoplasmic environment continuously,resulting in the sequential release of diPTX and PTX when it was phagocytosed by tumor cells.Meanwhile,PTX showed almost no release under physiological condition(pH 7.4),which effectively inhibited the undesirable premature release of PTX.More importantly,diPTX@Fe&TA could suppress the growth of tumor effectively in vivo,along with negligible toxicity for organs.This work developed a simple and novel approach for the construction of a stepwise multiple stimuli-responsive drug delivery system with superior stability and satisfactory drug loading capacity to inhibit tumor growth effectively.

Metal-phenolic networks modified polyurethane as periosteum for bone regeneration

Treatment of bone defects still poses a great challenge in orthopedic clinics, and the vital role of periosteum in such processes has attracted widespread attention. However, studies focusing on the oxidative stress micro-environment with an artificial periosteum at the site of defect have been scarce. The intrinsic anti-oxidative properties and therapeutic potential for bone defects of metal-phenolic networks(MPNs)have provided a potential solution to this. Herein, we have developed a protocatechualdehyde + zinc ion(PCA+Zn^(Ⅱ)) MPN coating on a thermoplastic polyurethane membrane with a one-pot method to fabricate a new-type of periosteum with meritorious biocompatibility and abilities of modulating oxidative stress condition and promoting osteogenesis and mineralization for better bone regeneration, which has shown to be a promising strategy for constructing artificial periosteum with various MPNs.

A Biomimetic Surface for Infection-resistance through Assembly of Metal-phenolic Networks

Despite the fact that numerous infection-resistant surfaces have been developed to prevent bacterial colonization and biofilm formation, developing a stable, highly antibacterial and easily produced surface remains a technical challenge. As a crucial structural component of biofilm, extracellular DNA（eDNA） can facilitate initial bacterial adhesion, subsequent development, and final maturation. Inspired by the mechanistic pathways of natural enzymes（deoxyribonuclease）, here we report a novel antibacterial surface by employing cerium（Ce（Ⅳ）） ion to mimic theDNA-cleavage ability of natural enzymes. In this process, the coordination chemistry of plant polyphenols and metal ions was exploited to create an in situ metal-phenolic film on substrate surfaces. Tannic acid（TA） works as an essential scaffold and Ce（Ⅳ） ion acts as both a cross-linker and a destructor of eDNA. The Ce（Ⅳ）-TA modified surface exhibited highly enhanced bacteria repellency and biofilm inhibition when compared with those of pristine or Fe（Ⅲ）-TA modified samples. Moreover, the easily produced coatings showed high stability under physiological conditions and had nontoxicity to cells for prolonged periods of time. This as-prepared DNA-cleavage surface presents versatile and promising performances to combat biomaterial-associated infections.

Hierarchical metal-phenolic-polyplex assembly toward superwetting membrane for high-flux and antifouling oil-water separation

Superwetting membranes have emerged as promising materials for the efficient treatment of oily wastewater.Typically,superwetting membranes can be developed by ingeniously chemical modification and topographical structuration of microporous membranes.Herein,we report the hierarchical assembly of metal-phenolic-polyplex coating to manipulate membrane surface superwettability by integrating metal-phenolic(Fe^(Ⅲ)-tannic acid(TA))assembly with polyplex(tannic acid-polyethylenimine(PEI))assembly.The proposed Fe-TA-PEI coating can be deposited on microporous membrane via simply dipping into Fe^(Ⅲ)-TA-PEI co-assembly solution.Based on the catechol chemistry,the coordination complexation of Fe^(Ⅲ)and TA develops metal-phenolic networks to provide hydrophilic chemistries,and the electrostatic complexation of TA and PEI generates nanoconjugates to impart hierarchical architectures.Benefiting from the synergy of hydrophilic chemistries and hierarchical architectures,the resulting PVDF/Fe-TA-PEI membrane exhibits excellent superhydrophilicity(~0°)underwater superoleophobicity(~150°)and superior anti-oil-adhesion capability.The superhydrophilicity of PVDF/Fe-TA-PEI membrane greatly promotes membrane permeability,featuring water fluxes up to 5860 L m^(-2)h^(-1).The underwater superoleophobicity of PVDF/Fe-TA-PEI membrane promises potential flux(3393 L m^(-2)h^(-1)),high separation efficiency(99.3%)and desirable antifouling capability for oil-in-water emulsion separation.Thus,we highlight the reported hierarchical metal-phenolic-polyplex assembly as a straightforward and effective strategy that enables the synchronous modulation of surface chemistry and topography toward superwetting membranes for promising high-flux and antifouling oil-water separation.

Co-delivery of enzymes and photosensitizers via metal-phenolic network capsules for enhanced photodynamic therapy

The intrinsic hypoxic tumor microenvironment and limited accumulation of photosensitizers(PSs) result in unsatisfied efficiency of photodynamic therapy(PDT).To enhance the PDT efficiency against solid tumors,a functional oxygen self-supplying and PS-delivering nanosystem is fabricated via the combination of catalase(CAT),chlorin e6(Ce6) and metal-phenolic network(MPN) capsule.It is demonstrated that the CAT encapsulated in the capsules(named CCM capsules) could catalyze the degradation of hydrogen peroxide(H;O;) to produce molecular oxygen(O;),which could be converted into cytotoxicity reactive oxygen species(ROS) by surface-loaded Ce6 under 660 nm laser irradiation,leading to synergistic anticancer effects in vitro and in vivo.Therefore,the application of CCM capsule could be a promising strategy to improve PDT effectiveness.

Alloyed nanostructures integrated metal-phenolic nanoplatform for synergistic wound disinfection and revascularization

New materials for combating bacteria-caused infection and promoting the formation of microvascular networks during wound healing are of vital importance.Although antibiotics can be used to prevent infection,treatments that can disinfect and accelerate wound healing are scarce.Herein,we engineer a coating that is both highly compatible with current wound dressing substrates and capable of simultaneously disinfecting and revascularizing wounds using a metal-phenolic nanoplatform containing an alloyed nanostructured architecture(Ag@Cu-MPNNC).The alloyed nanostructure is formed by the spontaneous co-reduction and catalytic disproportionation reaction of multiple metal ions on a foundation metal-phenolic supramolecular layer.This synergistic presence of metals greatly improves the antibacterial activity against both Gram-negative and Gram-positive pathogenic bacteria,while demonstrating negligible cytotoxicity to normal tissue.In infected rat models,the Ag@Cu-MPNNC could kill bacteria efficiently,promoting revascularization and accelerate wound closure with no adverse side effects in infected in vivo models.In other words,this material acts as a combination therapy by inhibiting bacterial invasion and modulating bio-nano interactions in the wound.

Multifunctional Integrated Organic-Inorganic-Metal Hybrid Aerogel for Excellent Thermal Insulation and Electromagnetic Shielding Performance

Vehicles operating in space need to withstand extreme thermal and electromagnetic environments in light of the burgeoning of space science and technology.It is imperatively desired to high insulation materials with lightweight and extensive mechanical properties.Herein,a boron-silica-tantalum ternary hybrid phenolic aerogel(BSiTa-PA)with exceptional thermal stability,extensive mechanical strength,low thermal conductivity(49.6 mW m^(-1)K^(-1)),and heightened ablative resistance is prepared by an expeditious method.After extremely thermal erosion,the obtained carbon aerogel demonstrates noteworthy electromagnetic interference(EMI)shielding performance with an efficiency of 31.6 dB,accompanied by notable loading property with specific modulus of 272.8 kN·m kg^(-1).This novel design concept has laid the foundation for the development of insulation materials in more complex extreme environments.

Controlled-release hydrogel loaded with magnesium-based nanoflowers synergize immunomodulation and cartilage regeneration in tendon-bone healing

Tendon-bone interface injuries pose a significant challenge in tissue regeneration,necessitating innovative approaches.Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries.In this study,we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions(Mg^(2+)).We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles(Mg-PC)through a self-assembly process and integrated them into a two-component hydrogel.The hydrogel was composed of dopamine-modified hyaluronic acid(Dop-HA)and F127.To ensure controlled release and mitigate the“burst release”effect of Mg^(2+),we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel.This crosslinking strategy extended the release window of Mg^(2+)concentrations for up to 56 days.The resulting hydrogel(Mg-PC@Dop-HA/F127)exhibited favorable properties,including injectability,thermosensitivity and shape adaptability,making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites.Furthermore,the hydrogel sustained the release of Mg^(2+)and Procyanidins,which attracted mesenchymal stem and progenitor cells,alleviated inflammation,and promoted macrophage polarization towards the M2 phenotype.Additionally,it enhanced collagen synthesis and mineralization,facilitating the repair of the tendon-bone interface.By incorporating multilevel metal phenolic networks(MPN)to control ion release,these hybridized hydrogels can be customized for various biomedical applications.

Phenolic-enabled nanotechnology:a new strategy for central nervous system disease therapy

Polyphenolic compounds have received tremendous attention in biomedicine because of their good biocompatibility and unique physicochemical properties.In recent years,phenolic-enabled nanotechnology(PEN)has become a hotspot of research in the medical field,and many promising studies have been reported,especially in the application of central nervous system(CNS)diseases.Polyphenolic compounds have superior anti-inflammatory and antioxidant properties,and can easily cross the blood‒brain barrier,as well as protect the nervous system from metabolic damage and promote learning and cognitive functions.However,although great advances have been made in this field,a comprehensive review regarding PEN-based nanomaterials for CNS therapy is lacking.A systematic summary of the basic mechanisms and synthetic strategies of PEN-based nanomaterials is beneficial for meeting the demand for the further development of novel treatments for CNS diseases.This review systematically introduces the fundamental physicochemical properties of PEN-based nanomaterials and their applications in the treatment of CNS diseases.We first describe the different ways in which polyphenols interact with other substances to form high-quality products with controlled sizes,shapes,compositions,and surface chemistry and functions.The application of PEN-based nanomaterials in the treatment of CNS diseases is then described,which provides a reference for subsequent research on the treatment of CNS diseases.

Bacterial cellulose-based dressings with photothermal bactericidal activity and pro-angiogenic ability for infected wound healing

For most traditional wound dressings,it is challenging to simultaneously eliminate bacteria and promote angiogenesis to accelerate the healing process of bacteria-infected wounds.In this work,we develop a multifunctional dressing based on bacterial cellulose(BC)deposited with a tannic acid/Cu^(2+)ion/Mg^(2+)ion(TCM)complex film.Overall,the TCM complex exhibits robust interfacial adhesion to modify BC and good photothermal properties to effectively eradicate bacteria in the wound area under near-infrared(NIR)irradiation.The individual components of the TCM complex have several advantageous features for wound healing,such as antibacterial ability and negligible cytotoxicity;in particular,the released Cu^(2+)and Mg^(2+)ions are favorable for the proliferation,migration,and tube formation of endothelial cells in vitro.The results of in vivo experiments demonstrated that with the assistance of NIR irradiation,this composite dressing is more effective than traditional gauze or pristine BC dressing in promotion of angiogenesis and collagen deposition without causing remarkable inflammation,thereby accelerating the healing process of bacteria-infected full-thickness skin wounds.This work thus provides a simple and facile way to fabricate multifunctional BC-based dressings that could be potentially used for treating infected wounds.

Near infrared light-induced dynamic modulation of enzymatic activity through polyphenol-functionalized liquid metal nanodroplets

Dynamic manipulation of enzymatic activity is a challenging task for applications in chemical and pharmaceutical industries due to the difficult modification and variable conformation of various enzymes.Here, we report a new strategy for reversible dynamic modulation of enzymatic activity by near-infrared light-induced photothermal conversion based on polyphenol-functionalized liquid metal nanodroplets(LM). The metal-phenolic nanocoating not only provides colloidal stability of LM nanodroplets but also generates nanointerfaces for the assembly of various enzymes on the LM nanodroplets. Upon near infrared(NIR) irradiation, the localized microenvironmental heating through photothermal effect of the LM nanodroplets allows tailoring the enzymatic activity without affecting the bulk temperature. A library of functional enzymes, including proteinase K, glucoamylase, glucose oxidase, and Bst DNA polymerase, is integrated to perform a reversible control and enhanced activities even after five times of cycles, demonstrating great potential in bacterial fermentation, bacteriostasis, and target gene amplification.

Innovations and challenges of polyphenol-based smart drug delivery systems

Polyphenols,as widely existing natural bioactive products,provide a vast array of advanced biomedical applications attributing to their potential health benefits that linked to antioxidant,anti-inflammatory,immunoregulatory,neuroprotective,cardioprotective function,etc.The polyphenol compounds could dynamically interact and bind with diverse species(such as polymers,metal ions,biomacromolecules,etc.)via multiple interactions,including hydrogen bond,hydrophobic,π–π,and cation–πinteractions due to their unique chemical polyphenolic structures,providing far-ranging strategies for designing of polyphenol-based vehicles.Natural polyphenols emerged as multifaceted players,acting either as inherent therapeutics delivered to combat diverse diseases or as pivotal assemblies of drug delivery vehicles.In this review,we focused on the rational design and application of metal-phenolic network(MPN)based delivery systems,polyphenol-based coating films,polyphenol hollow capsules,polyphenolincorporated hydrogels,and polymer-polyphenol-based nanoparticles(NPs)in various diseases therapeutic,including cancer,infection,cardiovascular disease,neurodegenerative disease,etc.Additionally.the versatility and mechanisms of polyphenols in the field of biomacromolecules(e.g.,protein,peptide,nucleic acid,etc.)delivery and cell therapy have been comprehensively summarized.Going through the literature review,the remaining challenges of polyphenol-containing nanosystems need to be addressed are involved,including long-term stability,biosafety in vivo,feasibility of scale-up,etc.,which may enlighten the further developments of this field.This review provides perspectives in utilizing natural polyphenol-based biomaterials to rationally design next generation versatile drug delivery system in the field of biomedicine,which eventually benefits public health.

Rapid formation of metal-monophenolic networks on polymer membranes for oil/water separation and dye adsorption

Surface deposition based on metal-phenolic networks(MPNs) has received increasing interest in recent years. The catechol structure is generally considered to be essential to the formation of MPNs. Our most recent results have demonstrated that some kinds of monophenols can form MPNs on substrate surfaces.Herein, we report a fast and effective surface-coating system based on the coordination of 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid, a kind of monophenol, with Fe^(3+). Compared with other metal ions such as Cu^(2+)and Ni^(2+), Fe^(3+)with stronger electron acceptability can coordinate with the monophenol more strongly to form MPNs, and moreover, the deposition time significantly decreases to 40 min from generally 24 h. It is demonstrated that the deposition process is controlled by the coordination, Fe^(3+)hydrolysis, and deprotonation of the monophenol. The coatings endow substrates such as polypropylene microfiltration membrane with underwater superoleophobicity, which can be applied in oil/water separation with high separation efficiency and great long-term stability. In addition, the coated membranes are positively charged and thus are useful in selective adsorption of dyes. The present work not only provides a novel, fast, and one-step deposition method to fabricate MPNs, but also demonstrates that the fabrication efficiency of monophenol-based MPNs is comparable with that of polyphenol-based MPNs.