Preparation of Liposome Gel by Calcium Cross-Linking Induces the Long-Term Release of DOX to Improve the Antitumor Effect.

Doxorubicin (DOX) is one of the most commonly used anticancer drugs; however, its clinical application is greatly limited due to its toxicity and chemotherapy resistance. The delivery of DOX by liposomes (Lipos) can improve the blood circulation time in vivo and reduce toxic side effects, but the drug's accumulation in the tumor is often insufficient for effective treatment. In this study, we present a calcium cross-linked liposome gel for the encapsulation of DOX, demonstrating its superior long-term release capabilities compared to conventional Lipos. By leveraging this enhanced long-term release, we can enhance drug accumulation within tumors, ultimately leading to improved antitumor efficacy. Lipos were prepared using the thin-film dispersion method in this study. We utilized the ion-responsiveness of glutathione-gelatin (GSH-GG) to form the gel outside the Lipos and named the nanoparticles coated with GSH-GG on the outside of Lipos as Lipos@GSH-GG. The average size of Lipos@GSH-GG was around 342.9 nm, with a negative charge of -25.6 mV. The in vitro experiments revealed that Lipos@GSH-GG exhibited excellent biocompatibility and slower drug release compared to conventional Lipos. Further analysis of cellular uptake and cytotoxicity demonstrated that Lipos@GSH-GG loading DOX (DOX&Lipos@GSH-GG) exhibited superior long-term release effects and lower toxic side effects compared to Lipos loading DOX (DOX&Lipos). Additionally, the findings regarding the long-term release effect in vivo and the tumor accumulation within tumor-bearing mice of Lipos@GSH-GG suggested that, compared to Lipos, it demonstrated superior long-term release capabilities and achieved greater drug accumulation within tumors. In vivo antitumor efficacy experiments showed that DOX&Lipos@GSH-GG demonstrated superior antitumor efficacy to DOX&Lipos. Our study highlights Lipos@GSH-GG as a promising nanocarrier with the potential to enhance efficacy and safety by means of long-term release effects and may offer an alternative approach for effective antitumor therapy in the future.

Confined Cascade Metabolic Reprogramming Nanoreactor for Targeted Alcohol Detoxification and Alcoholic Liver Injury Management.

Alcoholic liver injury (ALI) is the leading cause of serious liver disease, whereas current treatments are mostly supportive and unable to metabolize alcohol directly. Here we report a metabolic reprogramming strategy for targeted alcohol detoxification and ALI management based on a confined cascade nanoreactor. The nanoreactor (named AA@mMOF) is designed by assembling natural enzymes of alcohol oxidase (AOx) and aldehyde dehydrogenase (ALDH) in the cavity of a mesoporous metal organic framework (mMOF) nanozyme with intrinsic catalase (CAT)-like activity. By conducting confined AOx/CAT/ALDH cascade reactions, AA@mMOF enables self-accelerated alcohol degradation (>0.5 mg·mL-1·h-1) with negligible aldehyde diffusion and accumulation, reprogramming alcohol metabolism and allowing high-efficiency detoxification. Administered to high-dose alcohol-intoxicated mice, AA@mMOF shows surprising liver targeting and accumulation performance and dramatically reduces blood alcohol concentration and rapidly reverses unconsciousness and acute liver injury to afford targeted alcoholism treatment. Moreover, AA@mMOF dramatically alleviates fat accumulation and oxidative stress in the liver of chronic alcoholism mice to block and reverse the progression of ALI. By conducting confined AOx/CAT/ALDH cascade reactions for high-efficiency alcohol metabolism reprogramming, AA@mMOF nanoreactor offers a powerful modality for targeted alcohol detoxification and ALI management. The proposed confined cascade metabolic reprogramming strategy provides a paradigm shift for the treatment of metabolic diseases.

Decoy Nanozymes Enable Multitarget Blockade of Proinflammatory Cascades for the Treatment of Multi-Drug-Resistant Bacterial Sepsis.

Sepsis is a life-threatening organ dysfunction characterized by severe systemic inflammatory response to infection. Effective treatment of bacterial sepsis remains a paramount clinical challenge, due to its astonishingly rapid progression and the prevalence of bacterial drug resistance. Here, we present a decoy nanozyme-enabled intervention strategy for multitarget blockade of proinflammatory cascades to treat multi-drug-resistant (MDR) bacterial sepsis. The decoy nanozymes (named MCeC@MΦ) consist mesoporous silica nanoparticle cores loaded with CeO2 nanocatalyst and Ce6 photosensitizer and biomimetic shells of macrophage membrane. By acting as macrophage decoys, MCeC@MΦ allow targeted photodynamic eradication of MDR bacteria and realize simultaneous endotoxin/proinflammatory cytokine neutralization. Meanwhile, MCeC@MΦ possess intriguing superoxide dismutase and catalase-like activities as well as hydroxyl radical antioxidant capacity and enable catalytic scavenging of multiple reactive oxygen species (ROS). These unique capabilities make MCeC@MΦ to collaboratively address the issues of bacterial infection, endotoxin/proinflammatory cytokine secretion, and ROS burst, fully cutting off the path of proinflammatory cascades to reverse the progression of bacterial sepsis. In vivo experiments demonstrate that MCeC@MΦ considerably attenuate systemic hyperinflammation and rapidly rescue organ damage within 1 day to confer higher survival rates (>75%) to mice with progressive MDR Escherichia coli bacteremia. The proposed decoy nanozyme-enabled multitarget collaborative intervention strategy offers a powerful modality for bacterial sepsis management and opens up possibilities for the treatment of cytokine storm in the COVID-19 pandemic and immune-mediated inflammation diseases.

Plasmonic Nanozymes: Leveraging Localized Surface Plasmon Resonance to Boost the Enzyme-Mimicking Activity of Nanomaterials.

Nanozymes, a type of nanomaterials that function similarly to natural enzymes, receive extensive attention in biomedical fields. However, the widespread applications of nanozymes are greatly plagued by their unsatisfactory enzyme-mimicking activity. Localized surface plasmon resonance (LSPR), a nanoscale physical phenomenon described as the collective oscillation of surface free electrons in plasmonic nanoparticles under light irradiation, offers a robust universal paradigm to boost the catalytic performance of nanozymes. Plasmonic nanozymes (PNzymes) with elevated enzyme-mimicking activity by leveraging LSPR, emerge and provide unprecedented opportunities for biocatalysis. In this review, the physical mechanisms behind PNzymes are thoroughly revealed including near-field enhancement, hot carriers, and the photothermal effect. The rational design and applications of PNzymes in biosensing, cancer therapy, and bacterial infections elimination are systematically introduced. Current challenges and further perspectives of PNzymes are also summarized and discussed to stimulate their clinical translation. It is hoped that this review can attract more researchers to further advance the promising field of PNzymes and open up a new avenue for optimizing the enzyme-mimicking activity of nanozymes to create superior nanocatalysts for biomedical applications.

Temperature-Ion-pH Triple Responsive Gellan Gum as In Situ Hydrogel for Long-Acting Cancer Treatment.

BACKGROUND: Promising cancer chemotherapy requires the development of suitable drug delivery systems (DDSs). Previous research has indicated that a hydrogel is a powerful DDS for tumor therapy and holds great potential to offer a feasible method for cancer management. METHODS: In this study, glutathione-gellan gum conjugate (GSH-GG) was synthesized through chemical reaction. Doxorubicin hydrochloride (DOX) was loaded into GSH-GG to accomplish DOX-loaded GSH-GG. The properties, injectability, drug release, and in vitro and in vivo anticancer effects of DOX-loaded GSH-GG were tested. RESULTS: DOX-loaded GSH-GG showed a temperature-ion dual responsive gelling property with good viscosity, strength, and injectability at an optimized gel concentration of 1.5%. In addition, lower drug release was found under acidic conditions, offering beneficial long-acting drug release in the tumor microenvironment. DOX-loaded GSH-GG presented selective action by exerting substantially higher cytotoxicity on cancer cells (4T1) than on normal epithelial cells (L929), signifying the potential of complete inhibition of tumor progression, without affecting the health quality of the subjects. CONCLUSIONS: GSH-GG can be applied as a responsive gelling material for delivering DOX for promising cancer therapy.

Liposome Loaded Ion/Temperature Dual Responsive Gellan Gum Hydrogel as Potential Nasal-To-Brain Delivery System.

Intranasal administration, which can bypass the blood-brain barrier (BBB), is widely recognized as a promising strategy for high-efficiency drug delivery to the brain. Herein, for the purpose of effectively delivering drugs to the brain via intranasal administration, glutathione (GSH)-modified gellan gum (GSH-GG) with ion/temperature dual responsive properties was synthesized and encapsulated on galanthamine hydrobromide (GH)-loaded liposomes (GH-Lipo) for effective GH delivery to the brain (GH-Lipo@GSH-GG). Our results demonstrated that GSH-GG greatly decreased the gelation temperature of GG from 44.0 °C to 22.1 °C without compromising its ion responsiveness. Moreover, GSH-GG had a good protection ability for GH-loaded liposomes without affecting its drug release. Most importantly, the finally obtained GH-Lipo@GSHGG showed acceptable targeted delivery of GH to the brain upon in vivo administration. Therefore, this formulation can be employed as a potential delivery system in nasal-to-brain delivery.

pH-switchable nanozyme cascade catalysis: a strategy for spatial-temporal modulation of pathological wound microenvironment to rescue stalled healing in diabetic ulcer.

The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial-temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe3O4-GOx). The Fe3O4-GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe3O4-GOx-instructed spatial-temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases.

Nanophysical Antimicrobial Strategies: A Rational Deployment of Nanomaterials and Physical Stimulations in Combating Bacterial Infections.

The emergence of bacterial resistance due to the evolution of microbes under antibiotic selection pressure, and their ability to form biofilm, has necessitated the development of alternative antimicrobial therapeutics. Physical stimulation, as a powerful antimicrobial method to disrupt microbial structure, has been widely used in food and industrial sterilization. With advances in nanotechnology, nanophysical antimicrobial strategies (NPAS) have provided unprecedented opportunities to treat antibiotic-resistant infections, via a combination of nanomaterials and physical stimulations. In this review, NPAS are categorized according to the modes of their physical stimulation, which include mechanical, optical, magnetic, acoustic, and electrical signals. The biomedical applications of NPAS in combating bacterial infections are systematically introduced, with a focus on their design and antimicrobial mechanisms. Current challenges and further perspectives of NPAS in the clinical treatment of bacterial infections are also summarized and discussed to highlight their potential use in clinical settings. The authors hope that this review will attract more researchers to further advance the promising field of NPAS, and provide new insights for designing powerful strategies to combat bacterial resistance.

Nanodot-doped peptide hydrogels for antibacterial phototherapy and wound healing.

Bacterial infection of wounds delays the healing process, increases the risk of chronic trauma associated with pain and complications, and offers a breeding ground for drug-resistant bacteria. A rapid and effective eradication of the bacterial species in the wound area is thus important. Herein, we designed a phototherapeutic antibacterial platform based on peptides and copper sulfide nanodots (CuS NDs) for multi-mechanistic eradication of bacteria colonized on the wound surface. The antimicrobial peptide weaves into a network in the form of a hydrogel, which supports CuS NDs to generate heat and produce reactive oxygen species (ROS) under the irradiation of near-infrared light (NIR). The heat and ROS generated in situ act as non-contact-based antibacterial factors and together with contact-based antimicrobial peptides cause irreversible membrane destruction, cell content damage, and thermal ablation of the bacteria. Lastly, nanodot-doped peptide hydrogels combined with collagen showed complete bacterial elimination and significantly accelerated wound healing in a splint-fixed mouse infection model.

Manganese dioxide nanozyme for reactive oxygen therapy of bacterial infection and wound healing.

Reactive oxygen species (ROS) are the weapons of neutrophiles against bacterial pathogens, and also the central effectors in reactive oxygen therapy for skin and soft tissue infection. Nanozymes that spontaneously generate ROS under physiological conditions are new antibacterials that hold promise towards multidrug resistant pathogens. The clinical use of the nanozymes is however limited by their low biocompatibility and toxicity in vivo. Here, we develop an oleic acid (OA) nanoemulsion template method for the one-pot synthesis of OA-manganese dioxide (MnO2) nanozyme. The OA-MnO2 nanozyme showed high stability and biocompatibility under physiological conditions with marked oxidase-like activity. The ROS generated by the OA-MnO2 nanozyme effectively kill the Gram-positive Staphylococcus aureus and the Gram-negative Escherichia coli strains. Moreover, the OA-MnO2 nanozyme shows promising abilities to prevent and destruct biofilm formation by Staphylococcus aureus, and result in superior in vivo antibacterial performance as compared to vancomycin. The reactive oxygen therapy based on OA-MnO2 nanozyme cures the infected skin and promotes wound healing in mice, manifesting its potential use in skin and soft tissue infection.

Gelatinase-responsive release of an antibacterial photodynamic peptide against Staphylococcus aureus.

Staphylococcus aureus (S. aureus) related staphylococcal infection is one of the most common types of hospital-acquired infections, which requires selective and effective treatment in clinical practice. Considering gelatinase as a characteristic feature of S. aureus, gelatinase-responsive release of the antibiotic reagent thereby can target the pathogenic S. aureus while sparing beneficial bacteria in the microflora. In this work, we design a hybrid antibacterial photodynamic peptide (APP, Ce6-GKRWWKWWRRPLGVRGC) based on the polycationic antimicrobial peptide GKRWWKWWRR by introducing a photosensitizer chlorin e6 (Ce6) at the N-terminus, a cysteine residue at the C-terminus, and a gelatinase cleavage site (PLGVRG) inserted between the C-terminal cysteine and the polycationic peptide. This multi-motif peptide assembles with gold nanoclusters (AuNc) via Au-thiol bonding and affords a gelatinase-responsive antibacterial photodynamic nanocomposite (GRAPN). In vitro results show that the gelatinase secreted by S. aureus can cleave and release APP from AuNc, thereby resulting in preferential killing of S. aureus over E. coli. In a mouse model of staphylococcal skin wound infection, by integrating gelatinase-responsive drug release and the synergistic effect of a photodynamic agent and APP, GRAPN exhibits a marked photodynamic antibacterial activity, effectively eradicates S. aureus infection, and promotes rapid healing of the infected wounds.

A transformable gold nanocluster aggregate-based synergistic strategy for potentiated radiation/gene cancer therapy.

Nano-radiosensitizers provide a powerful tool for cancer radiation therapy. However, their limited tumor retention/penetration and the inherent or adaptive radiation resistance of tumor cells hamper the clinical success of radiation therapy. Herein, we report a synergistic strategy for potentiated cancer radiation/gene therapy based on transformable gold nanocluster aggregates loaded with antisense oligonucleotide-targeting survivin mRNA (named AuNC-ASON). AuNC-ASON exhibited acidic pH-triggered structure splitting from a gold nanocluster aggregate (around 80 nm) to gold nanocluster (<2 nm), leading to the tumor microenvironment-responsive size transformation of the nano-radiosensitizer and activated release of the loaded antisense oligonucleotides to perform gene silencing. The in vitro experiments demonstrated that AuNC-ASON could amplify and improve the radio-sensitivity of tumor cells (the sensitization enhancement ratio was about 1.81) as a result of the synergistic effect of the transformable gold nanocluster radiosensitizer and survivin gene interference. Remarkably, the size transformation capability realized the high tumor retention/penetration and renal metabolism of AuNC-ASON in vivo and boosted the radio-susceptibility of cancer cells with the assistance of survivin gene interference, synergistically achieving potentiated tumor radiation/gene therapy. The proposed concept of transformable nano-radiosensitizer aggregate-based synergistic therapy can be utilized as a general strategy to guide the design of activatable multifunctional nanosystems for cancer theranostics.

Antibacterial Photodynamic Gold Nanoparticles for Skin Infection.

Damage or injury to the skin creates wounds that are vulnerable to bacterial infection, which in turn retards the process of skin regeneration and wound healing. In patients with severe burns and those with chronic diseases, such as diabetes, skin infection by multidrug-resistant bacteria can be lethal. Therefore, a broad-spectrum therapy to effectively eradicate bacterial infection through a mechanism different from that of antibiotics is much sought after. We successfully synthesized antibacterial photodynamic gold nanoparticles (AP-AuNPs), which are self-assembled nanocomposites of an antibacterial photodynamic peptide and poly(ethylene glycol) (PEG)-stabilized AuNPs. The AP-AuNPs exhibited aqueous and light stability, a satisfactory generation of reactive oxygen species (ROS), and a remarkable antibacterial effect toward both Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli upon light irradiation. Moreover, the synthesized nanocomposites significantly inhibited bacterial growth and biofilm formation in vitro. Photodynamic antibacterial treatment accelerated the wound-healing rate in S. aureus infections, mimicking staphylococcal skin infections. Using a combination of the bactericidal effect of a peptide, the photodynamic effect of a photosensitizer, and the multivalency clustering on AuNPs for maximal antibacterial effect under light irradiation, we synthesized AP-AuNPs as a wound-dressing nanomaterial in skin infections to promote wound healing. Our findings indicate a promising strategy in the management of bacterial infections resulting from damaged skin tissue, an aspect that has not been fully explored by our peers.

Antibacterial photodynamic peptides for staphylococcal skin infection.

As the barrier between the human body and the outside world, the skin is vulnerable to pathogenic microorganisms, especially when suffering from skin injuries such as burns. Staphylococcus aureus remains the most common type of bacteria that infects humans, and the surging drug resistance poses a major threat to the treatment of these infections. Here we report the development of antibacterial photodynamic peptides (APPs) that are constructed based on the covalent conjugation of an antibacterial peptide and the photosensitizer chlorin e6 (Ce6). Peptide conjugation significantly increases the photo-stability of Ce6, while retaining its ROS generation capability under photo-irradiation. The APPs combine the antibacterial activity of the peptide and the photodynamic therapy of Ce6, and under the assistance of mild laser irradiation, can eradicate bacterial infection and inhibit the formation of bacterial biofilms ex vivo. One of the APPs, (GKRWWKWWRR)2KGGK(Ce6)G, AMP2-Ce6, with Ce6 conjugated with the dimeric peptide, showed exceptional antibacterial activity with an MIC90 value around 3.2 µM without photo-irradiation and <0.1 µM with short light treatment. Supported by a hydrogel matrix composed of gelatin and recombinant human collagen III protein (rhCol III) mimicking the extracellular matrix of skin cells, AMP2-Ce6 efficiently accelerated the healing rate of wounds and improved the quality of wound healing in mice infected with Staphylococcus aureus. Altogether, here we report the development of antibacterial photodynamic peptides, which together with a regenerative matrix material exhibit an added effect against staphylococcal skin infection. This composite material holds promise as a new type of wound dressing material for skin infection and wound healing.

Enzyme-responsive turn-on nanoprobes for in situ fluorescence imaging and localized photothermal treatment of multidrug-resistant bacterial infections.

Sensitive diagnosis and elimination of multidrug-resistant bacterial infections at an early stage remain paramount challenges. Herein, we present a gelatinase-responsive turn-on nanoprobe for in situ near-infrared (NIR) fluorescence imaging and localized photothermal treatment (PTT) of in vivo methicillin-resistant Staphylococcus aureus (MRSA) infections. The designed nanoprobe (named AuNS-Apt-Cy) is based on gold nanostars functionalized with MRSA-identifiable aptamer and gelatinase-responsive heptapeptide linker (CPLGVRG)-cypate complexes. The AuNS-Apt-Cy nanoprobe is non-fluorescent in aqueous environments due to the fluorescence resonance energy transfer between the gold nanostar core and cypate dye. We demonstrate that the AuNS-Apt-Cy nanoprobe can achieve MRSA targeting and accumulation as well as gelatinase (overexpressed in MRSA environments)-responsive turn-on NIR fluorescence due to the cleavage of the CPLGVRG linker and localized in vitro PTT via a mechanism involving bacterial cell wall and membrane disruption. In vivo experiments show that the AuNS-Apt-Cy nanoprobe can enable rapid (1 h post-administration) and in situ turn-on NIR fluorescence imaging with high sensitivity (105 colony-forming units) in diabetic wound and implanted bone plate mouse models. Remarkably, the AuNS-Apt-Cy nanoprobe can afford efficient localized PTT of diabetic wound and implanted bone plate-associated MRSA infections under the guidance of turn-on NIR fluorescence imaging, showing robust capability for early diagnosis and treatment of in vivo MRSA infections. In addition, the nanoprobe exhibits negligible damage to surrounding healthy tissues during PTT due to its targeted accumulation in the MRSA-infected site, guaranteeing its excellent in vivo biocompatibility and solving the main bottlenecks that hinder the clinical application of PTT-based antibacterial strategies.

Glucose Oxidase-Loaded Antimicrobial Peptide Hydrogels: Potential Dressings for Diabetic Wound.

The wound of diabetic foot is difficult to heal, and in severe cases, diabetic patients have to undergo limb amputation even after wound management. Hyperglycemia-caused vascular dysfunction and serious wound bacterial infection are the two main causes of unhealed diabetic foot ulcers. Therefore, it would be of great benefit to rescue stalled healing in diabetic wound if the blood glucose concentration can be efficiently decreased while controlling the bacterial infection in diabetic wound. Herein, we report glucose oxidase (GOx)-loaded antimicrobial peptide hydrogels and investigate their potential as diabetic wound dressings. The antimicrobial hydrogels are formed by the selfassembly of a heptapeptide (IKYLSVN) driven by intermolecular hydrogen bonding and π-π stacking interaction. The loaded GOx can convert glucose into hydrogen peroxide (H2O2), thus reducing blood glucose concentration of diabetic patients. At the same time, the produced H2O2 is antimicrobial and can combat bacterial infection in diabetic wound together with the antimicrobial hydrogels. Microscopic morphology observation of hydrogel shows uniform fibers with approximately 40 nm in size. The embedding rate can still reach 90% when the loading rate of the hydrogel loaded glucose oxidase is 12%. GOx is released by the swelling of the hydrogel based on the mechanism of free diffusion, and the cumulative release rate reaches 55%. Moreover, in vitro experiments showed that our GOx-loaded peptide hydrogel exhibits outstanding antimicrobial activity while can efficiently reduce glucose concentration of blood samples, showing great potential as promising diabetic wound dressings.

A nanowire-integrated thermoresponsive microfluidic platform for on-demand enrichment and colorimetric detection of pathogenic bacteria.

A nanowire-integrated thermoresponsive microfluidic platform is developed for bacterial enrichment and on-demand release. This microfluidic platform can enable selective and highly sensitive S. aureus detection in blood samples down to trace concentrations (40 CFU mL-1) by the naked eye with the help of a click reaction-assisted colorimetric assay.

pH-Switchable Antimicrobial Nanofiber Networks of Hydrogel Eradicate Biofilm and Rescue Stalled Healing in Chronic Wounds.

Biofilm infections can induce chronic inflammation and stall the normal orchestrated course of wound-healing cascades. Herein, pH-switchable antimicrobial hydrogel with nanofiber networks for biofilm eradication and rescuing stalled healing in chronic wounds is reported on the basis of the self-assembly of a designed octapeptide (IKFQFHFD) at neutral pH. This hydrogel is biocompatible and exhibits an acidic pH (pathological environment of infected chronic wounds)-switchable broad-spectrum antimicrobial effect via a mechanism involving cell wall and membrane disruption. The antimicrobial activity of hydrogel is derived from its acidic pH-dependent nanofiber network destabilization and activated release of IKFQFHFD, which is antimicrobial only at acidic pH due to the antimicrobial peptide-like molecular structure. In addition, supramolecular nanofiber networks loaded with drugs of cypate (photothermal agent) and proline (procollagen component) are further developed. In vitro experiments show that loaded drugs exhibit acidic pH (pH ∼ 5.5)-responsive release profiles, and synergistic biofilm eradication and subsequent healing cascade activation of cells proliferation are achieved on the basis of the supramolecular nanofiber networks. Remarkably, the nanofiber networks of hydrogel enable in vivo complete healing of MRSA biofilm infected wound in diabetic mice within 20 days, showing great potential as promising chronic wound dressings. The proposed synergistic strategy for eradicating biofilm and activating subsequent healing cascades may offer a powerful modality for the management of clinical chronic wounds.

Bacteria-Instructed Click Chemistry between Functionalized Gold Nanoparticles for Point-of-Care Microbial Detection.

Bacterial infections pose mounting public health concerns and cause an enormous medical and financial burden today. Rapid and sensitive detection of pathogenic bacteria at the point of care (POC) remains a paramount challenge. Here, we report a novel concept of bacteria-instructed click chemistry and employ it for POC microbial sensing. In this concept of bacteria-instructed click chemistry, we demonstrate for the first time that pathogenic bacteria can capture and reduce exogenous Cu2+ to Cu+ by leveraging their unique metabolic processes. The produced Cu+ subsequently acts as a catalyst to trigger the click reaction between gold nanoparticles (AuNPs) modified with azide and alkyne functional molecules, resulting in the aggregation of nanoparticles with a color change of the solution from red to blue. In this process, signal amplification from click chemistry is complied with the aggregation of functionalized AuNPs, thus presenting a robust colorimetric strategy for sensitive POC sensing of pathogenic bacteria. Notably, this colorimetric strategy is easily integrated in a smartphone app as a portable platform to achieve one-click detection in a mobile way. Moreover, with the help of the magnetic preseparation process, this smartphone app-assisted platform enables rapid (within 1 h) detection of Escherichia coli with high sensitivity (40 colony-forming units/mL) in the complex artificial sepsis blood samples, showing great potential for clinical early diagnosis of bacterial infections.

A NanoFlare-Based Strategy for In Situ Tumor Margin Demarcation and Neoadjuvant Gene/Photothermal Therapy.

Accurate tumor margin demarcation in situ remains a paramount challenge. Herein, a NanoFlare (also known as spherical-nucleic-acid technology) based strategy is reported for in situ tumor margin delineation by transforming and amplifying the pathophysiological redox signals of tumor microenvironment. The NanoFlare designed (named AuNS-ASON) is based on gold nanostar (AuNS) coated with a dense shell of disulfide bridge-inserted and cyanine dyes-labeled antisense oligonucleotides (ASON) targeting survivin mRNA. The unique anisotropic ASON-spike nanostructure endows the AuNS-ASON with universal cellular internalization of tumor cells, while the disulfide bridge inserted confers response specificity toward redox activation. In vitro experiments demonstrate that the AuNS-ASON can discriminate tumor cells rapidly with activated fluorescence signals (>100-fold) in 2 h, and further achieve synergistic gene/photothermal tumor cells ablation upon near-infrared laser irradiation. Remarkably, in situ tumor margin delineation with high accuracy and outstanding spatial resolution (<100 µm) in mice bearing different tumors is obtained based on the AuNS-ASON, providing intraoperative guidance for tumor resection. Moreover, the AuNS-ASON can enable efficient neoadjuvant gene/photothermal therapy before surgery to reduce tumor extent and increase resectability. The concept of NanoFlare-based microenvironment signal transformation and amplification could be used as a general strategy to guide the design of activatable nanoprobes for cancer theranostics.