Short Synthetic β‐Sheet Forming Peptide Amphiphiles as Broad Spectrum Antimicrobials with Antibiofilm and Endotoxin Neutralizing Capabilities

Although naturally occurring membrane lytic antimicrobial peptides (AMPs) and their analogs hold enormous promise for antibiotics‐resistant infectious disease therapies, significant challenges such as systemic toxicities, long peptide sequences, poor understanding of structure‐activity relationships, and the potential for compromising innate host defense immunity have greatly limited their clinical applicability. To improve the clinical potential of AMPs, a facile approach is adopted to design a series of short synthetic β‐sheet folding peptide amphiphiles comprised of short recurring (X₁Y₁X₂Y₂)_n‐NH₂ sequences, where X₁ and X₂: hydrophobic residues (Val, Ile, Phe or Trp), Y₁ and Y₂: cationic residues (Arg or Lys), and n: number of repeat units; with systematic variations to the cationic and hydrophobic residues to obtain optimized AMP sequences bearing minimal resemblance to naturally occurring sequences. The designed β‐sheet forming peptides exhibit broad spectrum antimicrobial activities against various clinically relevant microorganisms, including Gram‐positive Staphylococcus epidermidis and Staphylococcus aureus, Gram‐negative Escherichia coli and Pseudomonas aeruginosa, and yeast Candida albicans, with excellent selectivities for microbial membranes. Optimal synthetic peptides with n = 2 and n = 3 repeat units, i.e., (IRIK)₂‐NH₂ and (IRVK)₃‐NH₂, efficiently inhibit sessile biofilm bacteria growth leading to biomass reduction. Additionally, sequences with n = 3 repeat units effectively neutralize endotoxins while causing minimal cytotoxicities. Taken together, these findings clearly demonstrate that the rationally designed synthetic β‐sheet folding peptides are highly selective, non‐cytotoxic at antimicrobial levels and have tremendous potential for use as broad spectrum antimicrobial agents to overcome multidrug resistance in a wide range of localized, systemic, or external therapeutic applications.     

Magnetically Driven Silver‐Coated Nanocoils for Efficient Bacterial Contact Killing

The increasing threat of multidrug‐resistant bacterial strains against conventional antibiotic therapies represents a significant worldwide health risk and intensifies the need for novel antibacterial treatments. In this work, an effective strategy to target and kill bacteria using silver‐coated magnetic nanocoils is reported. The coil palladium (Pd) nanostructures are obtained by electrodeposition and selective dealloying, and subsequently coated with nickel (Ni) and silver (Ag) for magnetic manipulation and antibacterial properties, respectively. The efficiency of the nanocoils is tested in the treatment of Gram‐negative Escherichia coli (E. coli) and Gram‐positive methicillin‐resistant Staphylococcus aureus (S. aureus), both of which represent the leading multidrug‐resistant bacterial pathogens. The nanocoils show highly effective bacterial killing activity at low concentrations and in relatively short durations of treatment time. Three different investigation techniques, LIVE/DEAD assay, colony‐forming unit counting, and scanning electron microscope, reveal that the antibacterial activity is a result of bacterial membrane damage caused by direct contact with the nanocoil. The low cytotoxicity toward fibroblast cells along with the capability of precise magnetic locomotion makes the proposed nanocoil an ideal candidate to combat multidrug‐resistant bacteria in the field of biomedical and environmental applications.     

Genetically Engineered Chimeric Silk–Silver Binding Proteins

Composite or hybrid materials are commonly found in Nature, formed through the concentration and subsequent nucleation of ions upon organic templates that are most often protein based. Examples include the deposition of calcium containing salts in bone, teeth and the inner ear and iron oxide structures in magnetotactic bacteria. Biological organisms use a limited number of metal ions, the principal ones being calcium and iron, with lesser amounts of strontium, and barium. The ability to utilize other ions to generate composites offers the possibility of new material properties. New materials incorporating silver would be useful in the context of antimicrobial functions. Therefore, in the present study, a new route to such functionalized biomaterials is reported. Genetically engineered fusion proteins are created by the incorporation of nucleotides corresponding to short silver binding peptides identified by a combinatorial biopanning process into the consensus sequence of silk from the spider, Nephila clavipes. The resulting chimeric silk–silver binding proteins nucleated Ag ions from a solution of silver nitrate while the silk protein provided a stable template material which could be processed into films, fibers, and three‐dimensional scaffolds. The silk films inhibited microbial growth of both Gram‐positive and Gram‐negative microrganisms on agar plates and in liquid culture, thus highlighting the potential of these chimeric material systems as antimicrobial biomedical coatings.     

Synergistic Antimicrobial Capability of Magnetically Oriented Graphene Oxide Conjugated with Gold Nanoclusters

Bacterial resistance toward antibiotics has been a worldwide threat; one way to fight against the resistance is to develop a multimechanism antibacterial agent to achieve synergistic performance. Graphene oxide (GO) is an emerging antibacterial agent combining multiple mechanisms (physical insertion and chemical disruption), and its rich functional groups enable the complexation/conjugation of nanomaterials to further improve antibacterial performance. Herein, a synergistic antimicrobial agent is established through the assembly of paramagnetic holmium ions and gold nanoclusters (AuNCs) onto GO nanosheets. The assembled nanosheets can be vertically aligned under weak and practical magnetic fields (<0.5 T ), providing high‐density sharp edges with preferential orientation to effectively pierce the bacterial membrane. Also, the conjugated AuNCs are efficiently delivered into bacteria to induce high oxidative stress, which strongly disturbs bacterial metabolism, leading to the death of both Gram‐positive and Gram‐negative bacteria. The antibacterial agent uses both physical (via oriented GO) and chemical (via GO and AuNCs) mechanisms to achieve synergistic antimicrobial performance with low IC₅₀ values of 9.8 µg mL^?1 on the basis of GO and 0.39 × 10^?6 m on the basis of AuNCs. This multicomponent agent with dual antimicrobial mechanisms is expected to be a promising multifunctional‐antimicrobial agent with high biosafety.     

Genetically Engineered Phage Fibers and Coatings for Antibacterial Applications

Multifunctionality can be imparted to protein‐based fibers and coatings via either synthetic or biological approaches. Here, potent antimicrobial functionality of genetically engineered, phage‐based fibers and fiber coatings, processed at room temperature, is demonstrated. Facile genetic engineering of the M13 virus (bacteriophage) genome leverages the well‐known antibacterial properties of silver ions to kill bacteria. Predominant expression of negatively charged glutamic acid (E3) peptides on the pVIII major coat proteins of M13 bacteriophage enables solution‐based, electrostatic binding of silver ions and subsequent reduction to metallic silver along the virus length. Antibacterial fibers of micrometer‐scale diameters are constructed from such an E3‐modified phage via wet‐spinning and glutaraldehyde‐crosslinking of the E3‐modified viruses. Silverization of the free‐standing fibers is confirmed via energy dispersive spectroscopy and inductively coupled plasma atomic emission spectroscopy, showing ～0.61 µg cm^?1 of silver on E3–Ag fibers. This degree of silverization is threefold greater than that attainable for the unmodified M13–Ag fibers. Conferred bactericidal functionality is determined via live–dead staining and a modified disk‐diffusion (Kirby–Bauer) measure of zone of inhibition (ZoI) against Staphylococcus epidermidis and Escherichia coli bacterial strains. Live–dead staining and ZoI distance measurements indicate increased bactericidal activity in the genetically engineered, silverized phage fibers. Coating of Kevlar fibers with silverized E3 phage exhibits antibacterial effects as well, with relatively smaller ZoIs attributable to the lower degree of silver loading attainable in these coatings. Such antimicrobial functionality is amenable to rapid incorporation within fiber‐based textiles to reduce risks of infection, biofilm formation, or odor‐based detection, with the potential to exploit the additional electronic and thermal conductivity of fully silverized phage fibers and coatings.     

A Simple and Innovative Route to Prepare a Novel Carbon Nanotube/Prussian Blue Electrode and its Utilization as a Highly Sensitive H2O2 Amperometric Sensor

The utilization of iron‐based species (mainly metallic iron, hematite and magnetite) encapsulated into multi‐walled carbon nanotubes (CNTs) as reactants in an electrochemical synthesis is reported for the first time in this work. Prussian blue (PB) is electrosynthesized in a heterogeneous reaction between ferricyanide ions in aqueous solution and the iron‐species encapsulated into CNTs, resulting in novel CNT/PB paste electrodes. This innovative preparation route produces an intimate contact between the PB and the CNTs, which improves the stability and redox properties of PB. The PB formation and the chemical interaction between the PB and the CNTs are confirmed by Raman spectroscopy. The electrode is employed as a hydrogen peroxide amperometric sensor, resulting in a very low limit of detection (1.94 × 10^?8 mol L^?1) and very high sensitivity (15.3 A cm^?2 M ^?1).     

Biosynthesis of Zinc Substituted Magnetite Nanoparticles with Enhanced Magnetic Properties

The magnetic moments of magnetite nanoparticles are dramatically enhanced through the addition of zinc in a microbiologically driven synthesis procedure. The particles are produced through the reduction of Fe(III)‐compounds containing Zn(II) by the iron reducing bacterium Geobacter sulfurreducens. Results indicate a significant increase in the saturation magnetization by over 50% compared to magnetite at both room and low temperatures for relatively minor quantities of zinc substitution. A maximum saturation magnetization of nearly 100 emu g^?1 of sample is measured at room temperature. Analysis of the cation site ordering reveals a complex dependence on the Zn content, with the combined effect of Zn substitution of Fe³⁺ ions on tetrahedral sites, together with Fe²⁺ cation oxidation, leading to the observed magnetization enhancement for low Zn doping levels. The improved magnetic properties give superior performance in MRI applications with an MRI contrast enhancement among the largest values reported, being more than 5 times larger than a commercial contrast agent (Feridex) measured under identical conditions. The synthesis technique applied here involves an environmentally benign route and offers the potential to tune the magnetic properties of magnetic nanoparticles, with increased overall magnetization desirable for many different commercial applications.     

Self‐Defensive Biomaterial Coating Against Bacteria and Yeasts: Polysaccharide Multilayer Film with Embedded Antimicrobial Peptide

Prevention of pathogen colonization of medical implants is a major medical and financial issue since infection by microorganisms constitutes one of the most serious complications after surgery or critical care. Immobilization of antimicrobial molecules on biomaterials surfaces is an efficient approach to prevent biofilm formation. Herein, the first self‐defensive coating against both bacteria and yeasts is reported, where the release of the antimicrobial peptide is triggered by enzymatic degradation of the film due to the pathogens themselves. Biocompatible and biodegradable polysaccharide multilayer films based on functionalized hyaluronic acid by cateslytin (CTL), an endogenous host‐defensive antimicrobial peptide, and chitosan (HA‐CTL‐C/CHI) are deposited on a planar surface with the aim of designing both antibacterial and antifungal coating. After 24 h of incubation, HA‐CTL‐C/CHI films fully inhibit the development of Gram‐positive Staphylococcus aureus bacteria and Candida albicans yeasts, which are common and virulent pathogens agents encountered in care‐associated diseases. Hyaluronidase, secreted by the pathogens, leads to the film degradation and the antimicrobial action of the peptide. Furthermore, the limited fibroblasts adhesion, without cytotoxicity, on HA‐CTL‐C/CHI films highlights a medically relevant application to prevent infections on catheters or tracheal tubes where fibrous tissue encapsulation is undesirable.     

Dendritic Fe3O4@Poly(dopamine)@PAMAM Nanocomposite as Controllable NO‐Releasing Material: A Synergistic Photothermal and NO Antibacterial Study

Nowadays, antibiotic abuse increases the emergence of multidrug‐resistant bacterial strains, which is the major reason for the failure of conventional antibiotic therapies. Therefore, developing novel antibacterial materials or therapies is an urgent demand. In the present study, photothermal and NO‐releasing properties are integrated into a single nanocomposite to realize more efficient bactericidal effects. To this end, polydopamine (PDA) coated iron oxide nanocomposite (Fe₃O₄@PDA) is used as a photoconversion agent and the core, first three generation dendritic poly(amidoamine) (PAMAM‐G3) is grafted on the surface of Fe₃O₄@PDA, and subsequently NO is loaded with the formation of NONOate. The resultant Fe₃O₄@PDA@PAMAM@NONOate displays controllable NO release property under intermittent 808 nm laser irradiation and excellent bacteria‐separation efficiency. Moreover, excellent synergistic photothermal and NO antibacterial effects are observed against both Gram‐negative Escherichia coli and Gram‐positive Staphylococcus aureus, where bacterial viability and biofilm are significantly reduced. An antibacterial mechanism study reveals that the materials first adsorb onto the bacterial membrane, then cause damage to the membrane by the increased local temperature and the released NO under laser irradiation conditions, finally leak the intracellular components like DNA and induce bacteria death. The work provides a novel way for designing of antibacterial materials with higher efficiency.     

Synthesis and Characterization of Iron/Iron Oxide Core/Shell Nanocubes

A simple method for the preparation of iron/iron oxide nanoparticles with core/shell cubic morphology is presented. The synthesis of the nanocubes was carried out through decomposition of a preformed iron oleate complex at high temperature. Although this procedure has been shown previously to produce monodisperse magnetite spheres,^[1] the use of squalene as a solvent and the presence of sodium oleate was found to induce cube formation. A detailed high‐resolution transmission electron microscopy (HRTEM) analysis of the nanocubes was performed for structural characterization. The core/shell structure, an iron core surrounded by magnetite (Fe₃O₄) shell, was confirmed by fast Fourier transform (FFT) filtering analysis. The results obtained by HRTEM analysis are in agreement with X‐ray Photoelectron Spectroscopy (XPS) and magnetic analysis. The Fe nanocubes are superparamagnetic at room temperature with a saturation magnetization M_S = 101 A m² kg^–1 and magnetic anisotropy density K_eff = 1.6 × 10⁵ J m^–3 at low temperatures.     

Synthesis of Nearly Monodisperse Iron Oxide and Oxyhydroxide Nanocrystals

Uniform magnetite, hematite, and goethite nanocrystals were prepared through an attractive method based on an oleic acid/alcohol/water system. By adjusting the synthetic parameters (base concentration, alcohol content, categories of alcohols, etc.), the controlled synthesis of uniform magnetite, hematite, and goethite nanocrystals can be easily achieved. Detailed investigations on the effect of the experimental parameters on the morphology of the final products and the phase transitions among the magnetite, hematite, and goethite phases were carried out. Finally, a method of doping other metal ions into magnetite was developed and the magnetic properties of magnetite doped with different metal elements were studied.     

Liquid Crystal Emulsions as the Basis of Biological Sensors for the Optical Detection of Bacteria and Viruses

A versatile sensing method based on monodisperse liquid crystal (LC) emulsion droplets detects and distinguishes between different types of bacteria (Gram +ve and ?ve) and viruses (enveloped and non‐enveloped). LCs of 4‐cyano‐4'‐pentylbiphenyl transition from a bipolar to radial configuration when in contact with Gram ?ve bacteria (E. coli) and lipid‐enveloped viruses (A/NWS/Tokyo/67). This transition is consistent with the transfer of lipid from the organisms to the interfaces of the micrometer‐sized LC droplets. In contrast, a transition to the radial configuration is not observed in the presence of Gram +ve bacteria (Bacillus subtilis and Micrococcus luteus) and non‐enveloped viruses (M13 helper phage). The LC droplets can detect small numbers of E. coli bacteria (1–5) and low concentrations (10⁴ pfu mL^?1) of A/NWS/Tokyo/67 virus. Monodisperse LC emulsions incubated with phosholipid liposomes (similar to the E. coli cell wall lipid) reveal that the orientational change is triggered at an area per lipid molecule of ～46 Ų on an LC droplet (～1.6 × 10⁸ lipid molecules per droplet). This approach represents a novel means to sense and differentiate between types of bacteria and viruses based on their cell‐wall/envelope structure, paving the way for the development of a new class of LC microdroplet‐based biological sensors.     

Novel Magnetic Hydroxyapatite Nanoparticles as Non‐Viral Vectors for the Glial Cell Line‐Derived Neurotrophic Factor Gene

Nanoparticles (NPs) of synthetic hydroxyapatite (Hap) and natural bone mineral (NBM) are rendered magnetic by treatment with iron ions using a wet‐chemical process. The magnetic NPs (mNPs), which are about 300 nm in diameter, display superparamagnetic properties in a superconducting quantum interference device, with a saturation magnetization of about 30 emu g^?1. X‐ray diffraction and transmission electron microscopy reveal that the magnetic properties of the NPs are the result of the hetero‐epitaxial growth of magnetite on the Hap and NBM crystallites. The mNPs display a high binding affinity for plasmid DNA in contrast to magnetite NPs which do not bind the plasmid well. The mHap and mNBM NPs result in substantial increases in the transfection of rat marrow‐derived mesenchymal stem cells with the gene for glial cell line‐derived neurotrophic factor (GDNF), with magnetofection compared to transfection in the absence of a magnet. The amount of GDNF recovered in the medium approaches therapeutic levels despite the small amount of plasmid delivered by the NPs.     

Hierarchically Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation

Iron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging, guidance under remote fields, heat generation, and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub‐micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra‐small super‐paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers. These nanoconstructs exhibit transversal relaxivities up to ≈10 times (r ₂ ≈ 835 mm ^?1 s^?1) higher than conventional USPIOs and, under external magnetic fields, collectively cooperate to amplify tumor accumulation. The boost in r ₂ relaxivity arises from the formation of mesoscopic USPIO clusters within the porous matrix, inducing a local reduction in water molecule mobility as demonstrated via molecular dynamics simulations. The cooperative accumulation under static magnetic field derives from the large amount of iron that can be loaded per nanoconstuct (up to ≈65 fg) and the consequential generation of significant inter‐particle magnetic dipole interactions. In tumor bearing mice, the silicon‐based nanoconstructs provide MRI contrast enhancement at much smaller doses of iron (≈0.5 mg of Fe kg^?1 animal) as compared to current practice.     

Shining Light on Multidrug-Resistant Bacterial Infections: Rational Design of Multifunctional Organosilver-Based AIEgen Probes as Light-Activated Theranostics for Combating Biofilms and Liver Abscesses

The intricate environment of biofilms provides a heaven for bacteria to escape antibiotic eradication, leading to persistent chronic infections. Therefore, it is urgently needed to develop effective therapies to combat biofilm-associated infections. To address this problem, a series of antimicrobial agents are designed and synthesized utilizing triphenylamine imidazole silver complexes ( TPIMS ). Due to the photoactivated release of Ag⁺ coupled with aggregation-induced emission (AIE) properties and efficient ¹O₂ generation, TPIMS exhibits excellent visual diagnostic capabilities and potent broad-spectrum antimicrobial activity, showing antimicrobial efficacy against both Gram (+) and Gram (−) bacteria. Additionally, TPIMS shows extraordinary antibacterial performance and biofilm resistance against methicillin-resistant Staphylococcus aureus (MRSA), with reduced potential for resistance thanks to the synergistic effect of phototoxicity and dark toxicity. Notably, among the TPIMS variants tested, TPIMS-8 has demonstrated exceptional curative ability against resistant bacterial biofilm infections in vivo with minimal side effects. Furthermore, it is applied to clinical samples from infected patients and the results indicated that TPIMS-8 is able to achieve excellent bacterial-specific detection and superior killing of drug-resistant bacteria even in complex systems, demonstrating its great potential for clinical applications. This study presents a promising foundation for the development of advanced antimicrobial therapeutics targeting multidrug-resistant bacteria and biofilm-associated infections.     

Hybrids of Magnetic Nanoparticles with Double‐Hydrophilic Core/Shell Cylindrical Polymer Brushes and Their Alignment in a Magnetic Field

The synthesis of double‐hydrophilic core/shell cylindrical polymer brushes (CPBs), their hybrids with magnetite nanoparticles, and the directed alignment of these magnetic hybrid cylinders by a magnetic field are demonstrated. Consecutive grafting from a polyinitiator poly(2‐(2‐bromoisobutyryloxy)ethyl methacrylate) (PBIEM) of tert‐butyl methacrylate (tBMA) and oligo(ethylene glycol) methacrylate (OEGMA) using atom‐transfer radical polymerization (ATRP) and further de‐protection yields core/shell CPBs with poly(methacrylic acid) (PMAA) as the core and POEGMA as the shell, which is evidenced by ¹H NMR, gel permeation chromatography (GPC), and dynamic and static light scattering (DLS and SLS). The resulting core/shell brush is well soluble in water and shows a pH responsiveness because of its weak polyelectrolyte core. Pearl‐necklace structures are observed by cryogenic transmission electron microscopy (cryo‐TEM) at pH 4, while at pH 7, these structures disappear owing to the ionization of the core. A similar morphology is also found for the polychelate of the core/shell CPBs with Fe³⁺ ions. Superparamagnetic magnetite nanoparticles have also been prepared and introduced into the core of the brushes. The hybrid material retains the superparamagnetic property of the magnetite nanoparticles, which is verified by superconducting quantum interference device (SQUID) magnetization measurements. Large‐scale alignment of the hybrid cylinders in relatively low magnetic fields (40–300 mT) can easily be performed when deposited on a surface. which is clearly revealed by the atomic force microscopy (AFM) and TEM measurements.     

Natural Hematite for Next‐Generation Solid Oxide Fuel Cells

Natural hematite ore is used as a novel electrolyte material for advanced solid oxide fuel cells (SOFCs). This hematite‐based system exhibits a maximum power density of 225 mW cm^?2 at 600 °C and reaches 467 mW cm^?2 when the hematite is mixed with perovskite‐structured La_0.6Sr_0.4Co_0.2Fe_0.8O_3–δ. These results demonstrate that natural materials for next‐generation SOFCs can influence the multiutilization of natural resources, thereby affecting the environment and energy sustainability.     

Carbon Coated Fe3O4 Nanospindles as a Superior Anode Material for Lithium‐Ion Batteries

Carbon‐coated Fe₃O₄ nanospindles are synthesized by partial reduction of monodispersed hematite nanospindles with carbon coatings, and investigated with scanning electron microscopy, transmission electron microscopy, X‐ray diffraction, and electrochemical experiments. The Fe₃O₄? C nanospindles show high reversible capacity (～745 mA h g^?1 at C/5 and ～600 mA h g^?1 at C/2), high coulombic efficiency in the first cycle, as well as significantly enhanced cycling performance and high rate capability compared with bare hematite spindles and commercial magnetite particles. The improvements can be attributed to the uniform and continuous carbon coating layers, which have several functions, including: i) maintaining the integrity of particles, ii) increasing the electronic conductivity of electrodes leading to the formation of uniform and thin solid electrolyte interphase (SEI) films on the surface, and iii) stabilizing the as‐formed SEI films. The results give clear evidence of the utility of carbon coatings to improve the electrochemical performance of nanostructured transition metal oxides as superior anode materials for lithium‐ion batteries.     

Antimicrobial Gallium‐Doped Phosphate‐Based Glasses

Novel quaternary gallium‐doped phosphate‐based glasses (1, 3, and 5 mol % Ga₂O₃) were synthesized using a conventional melt quenching technique. The bactericidal activities of the glasses were tested against both Gram‐negative (Escherichia coli and Pseudomonas aeruginosa) and Gram‐positive (Staphylococcus aureus, methicillin‐resistant Staphylococcus aureus, and Clostridium difficile) bacteria. Results of the solubility and ion release studies showed that these glass systems are unique for controlled delivery of Ga³⁺. ⁷¹Ga NMR measurements showed that the gallium is mostly octahedrally coordinated by oxygen atoms, whilst FTIR spectroscopy provided evidence for the presence of a small proportion of tetrahedral gallium in the samples with the highest gallium content. FTIR and Raman spectra also afford an insight into the correlation between the structure and the observed dissolution behavior via an understanding of the atomic‐scale network bonding characteristics. The results confirmed that the net bactericidal effect was due to Ga³⁺, and a concentration as low as 1 mol % Ga₂O₃ was sufficient to mount a potent antibacterial effect. The dearth of new antibiotics in development makes Ga³⁺ a potentially promising new therapeutic agent for pathogenic bacteria including MRSA and C. difficile.     

Hybrid of Iron Nitride and Nitrogen‐Doped Graphene Aerogel as Synergistic Catalyst for Oxygen Reduction Reaction

It is extremely desirable but challenging to create highly active, stable, and low‐cost catalysts towards oxygen reduction reaction to replace Pt‐based catalysts in order to perform the commercialization of fuel cells. Here, a novel iron nitride/nitrogen doped‐graphene aerogel hybrid, synthesized by a facile two‐step hydrothermal process, in which iron phthalocyanine is uniformly dispersed and anchored on graphene surface with the assist of π–π stacking and oxygen‐containing functional groups, is reported. As a result, there exist strong interactions between Fe _x N nanoparticles and graphene substrates, leading to a synergistic effect towards oxygen reduction reaction. It is worth noting that the onset potential and current density of the hybrid are significantly better and the charge transfer resistance is much lower than that of pure nitrogen‐doped graphene aerogel, free Fe _x N and their physical mixtures. The hybrid also exhibits comparable catalytic activity as commercial Pt/C at the same catalyst loading, while its stability and resistance to methanol crossover are superior. Interestingly, it is found that, apart from the active nature of the hybrid, the large surface area and porosity are responsible for its excellent onset potential and the high density of Fe–N–C sties and small size of Fe _x N particles boost charge transfer rate.