GSH/pH Cascade-Responsive Nanoparticles Eliminate Methicillin-Resistant Staphylococcus aureus Biofilm via Synergistic Photo-Chemo Therapy.

Bacterial biofilm infection threatens public health, and efficient treatment strategies are urgently required. Phototherapy is a potential candidate, but it is limited because of the off-targeting property, vulnerable activity, and normal tissue damage. Herein, cascade-responsive nanoparticles (NPs) with a synergistic effect of phototherapy and chemotherapy are proposed for targeted elimination of biofilms. The NPs are fabricated by encapsulating IR780 in a polycarbonate-based polymer that contains disulfide bonds in the main chain and a Schiff-base bond connecting vancomycin (Van) pendants in the side chain (denoted as SP-Van@IR780 NPs). SP-Van@IR780 NPs specifically target bacterial biofilms in vitro and in vivo by the mediation of Van pendants. Subsequently, SP-Van@IR780 NPs are decomposed into small size and achieve deep biofilm penetration due to the cleavage of disulfide bonds in the presence of GSH. Thereafter, Van is then detached from the NPs because the Schiff base bonds are broken at low pH when SP@IR780 NPs penetrate into the interior of biofilm. The released Van and IR780 exhibit a robust synergistic effect of chemotherapy and phototherapy, strongly eliminate the biofilm both in vitro and in vivo. Therefore, these biocompatible SP-Van@IR780 NPs provide a new outlook for the therapy of bacterial biofilm infection.

Enhancing near-infrared II photodynamic therapy with nitric oxide for eradicating multidrug-resistant biofilms in deep tissues.

Nitric oxide (NO) enhanced photodynamic therapy (PDT) is a promising approach to overcome drug tolerance and resistance to biofilm but is limited by its short excitation wavelengths and low yield of reactive oxygen species (ROS). Herein, we develop a compelling degradable polymer-based near-infrared II (NIR-II, 1000-1700 nm) photosensitizer (PNIR-II), which can maintain 50 % PDT efficacy even under a 2.6 cm tissue barrier. Remarkably, PNIR-II is synthesized by alternately connecting the electron donor thiophene to the electron acceptors diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY), where the intramolecular charge transfer properties can be tuned to increase the intersystem crossover rate and decrease the internal conversion rate, thereby stabilizing the NIR-II photodynamic rather than photothermal effect. For exerting a combination therapy to eradicate multidrug-resistant biofilms, PNIR-II is further assembled into nanoparticles (NPs) with a synthetic glutathione-triggered NO donor polymer. Under 1064 nm laser radiation, NPs precisely release ROS and NO that triggered by over-expressed GSH in the biofilm microenvironment, thereby forming more bactericidal reactive nitrogen species (RNS) in vitro and in vivo in the mice model that orderly destroy biofilm of multidrug-resistant Staphylococcus aureus cultures from clinical patients. It thus provides a new outlook for destroy the biofilm of deep tissues.

Dual Coordination between Stereochemistry and Cations Endows Polyethylene Terephthalate Fabrics with Diversiform Antimicrobial Abilities for Attack and Defense.

Modification of fabrics by stereochemical antiadhesion strategies is an emerging approach to antimicrobial fabric finishing. However, a purely antiadhesive fabric cannot avoid the passive adhesion of pathogenic microorganisms. To address this issue, borneol 4-formylbenzoate (BF) with a stereochemical structure is introduced into a cationic polymer PEI-modified PET fabric by a simple two-step method. The obtained fabric exhibits remarkable features of high bactericidal activity, excellent resistance to bacterial adhesion, desirable fungal repellent performance, and low cytotoxicity. More impressively, this modified fabric not only effectively reduces microbial contamination during food preservation but also plays a role in avoiding infection and accelerating wound healing in the mouse wound model. The dual coordination between stereochemistry and cations is validated as a viable "attack and defense" antimicrobial strategy, providing an effective guide for diversiform antimicrobial designs.

An Acid-triggered Reactive and Enhanced Fluorescent Probe for Selective Detection of Al3+/H+ and its Application in Real Water Samples and Living Cells.

A reactive fluorescent "turn-on" probe (di-PIP) with imine-linked dual phenanthro[9,10-d]imidazole luminophore have been conveniently prepared as an Al3+ and H+ dual functional receptor. di-PIP displayed high selectivity and sensitivity towards Al3+ ion in DMF/HEPES accompanied by fluorescence blue-shift and a good linear relationship as well as a low detection limit of 30.5 nmol·L-1, which can root from the synergetic functions of the decomposition reaction of di-PIP promoted by acidic Al3+ and the coordination effect between decomposition product and Al3+. Intriguingly, it was found that hydrogen ion H+ can be sufficient for simulating the fluorescence enhancing of di-PIP. 1H NMR titration and MS analyses for elucidation of the intermediate structure further revealed that the acid-triggered decomposition reaction resulted in the rapid, and sensitive sensing to Al3+ and H+. In addition, the probe di-PIP could be successfully applied to the detection of Al3+ in real water samples, and also utilized to visualize Al3+ and H+ in the living cells.

Targeted Anti-Biofilm Therapy: Dissecting Targets in the Biofilm Life Cycle.

Biofilm is a crucial virulence factor for microorganisms that causes chronic infection. After biofilm formation, the bacteria present improve drug tolerance and multifactorial defense mechanisms, which impose significant challenges for the use of antimicrobials. This indicates the urgent need for new targeted technologies and emerging therapeutic strategies. In this review, we focus on the current biofilm-targeting strategies and those under development, including targeting persistent cells, quorum quenching, and phage therapy. We emphasize biofilm-targeting technologies that are supported by blocking the biofilm life cycle, providing a theoretical basis for design of targeting technology that disrupts the biofilm and promotes practical application of antibacterial materials.

Dual-Cascade Responsive Nanoparticles Enhance Pancreatic Cancer Therapy by Eliminating Tumor-Resident Intracellular Bacteria.

The limited drug penetration and robust bacteria-mediated drug inactivation in pancreatic cancer result in the failure of chemotherapy. To fight against these issues, a dual-cascade responsive nanoparticle (sNP@G/IR) that can sequentially trigger deep penetration, killing of intratumor bacteria, and controlled release of chemo-drug, is reported. sNP@G/IR consists of a hyaluronic acid (HA) shell and glutathione (GSH)-responsive polymer-core (NP@G/IR), that encapsulates gemcitabine (Gem) and photothermal agent (IR1048). The polymer core, as an antibiotic alternative, is tailored to exert optimal antibacterial activity and selectivity. sNP@G/IR actively homes in on the tumor due to the CD44 targeting of the HA shell, which is subsequently degraded by the hyaluronidase in the extracellular matrix. The resultant NP@G/IR in decreased size and reversed charge facilitates deep tumor penetration. After cellular endocytosis, the exposed guanidine on NP@G/IR kills intracellular bacteria through disrupting cell membranes. Intracellular GSH further triggers the controlled release of the cargo. Thus, the protected Gem eventually induces cell apoptosis. Under laser irradiation, the hyperthermia of IR1048 helps further elimination of tumors and bacteria. Moreover, sNP@G/IR activates immune response, thereby reinforcing anticancer capacity. Therefore, this dual-cascade responsive sNP@G/IR eliminates tumor-resident intracellular bacteria and augments drug delivery efficacy, providing a new avenue for improving cancer therapy.

Cascade-Targeting Poly(amino acid) Nanoparticles Eliminate Intracellular Bacteria via On-Site Antibiotic Delivery.

Intracellular bacteria in latent or dormant states tolerate high-dose antibiotics. Fighting against these opportunistic bacteria has been a long-standing challenge. Herein, the design of a cascade-targeting drug delivery system (DDS) that can sequentially target macrophages and intracellular bacteria, exhibiting on-site drug delivery, is reported. The DDS is fabricated by encapsulating rifampicin (Rif) into mannose-decorated poly(α-N-acryloyl-phenylalanine)-block-poly(ß-N-acryloyl-d-aminoalanine) nanoparticles, denoted as Rif@FAM NPs. The mannose units on Rif@FAM NPs guide the initial macrophage-specific uptake and intracellular accumulation. After the uptake, the detachment of mannose in acidic phagolysosome via Schiff base cleavage exposes the d-aminoalanine moieties, which subsequently steer the NPs to escape from lysosomes and target intracellular bacteria through peptidoglycan-specific binding, as evidenced by the in situ/ex situ co-localization using confocal, flow cytometry, and transmission electron microscopy. Through the on-site Rif delivery, Rif@FAM NPs show superior in vitro and in vivo elimination efficiency than the control groups of free Rif or the DDSs lacking the macrophages- or bacteria-targeting moieties. Furthermore, Rif@FAM NPs remodel the innate immune response of the infected macrophages by upregulating M1/M2 polarization, resulting in a reinforced antibacterial capacity. Therefore, this biocompatible DDS enabling macrophages and bacteria targeting in a cascade manner provides a new outlook for the therapy of intracellular pathogen infection.

Inserting Menthoxytriazine into Poly(ethylene terephthalate) for Inhibiting Microbial Adhesion.

Antimicrobial modification of poly(ethylene terephthalate) (PET) is effective in preventing the adhesion and growth of microorganisms on its surface. However, few methods are available to modify PET directly at its backbone to impart the antimicrobial effect. Herein, menthoxytriazine-modified PET (PMETM) based on the stereochemical antimicrobial strategy was reported. This novel PET was prepared by inserting menthoxytriazine into the PET backbone. The antibacterial adhesion test and the antifungal landing test were employed to confirm the antiadhesion ability of PMETM. PMETM could effectively inhibit the adhesion of bacteria, with inhibition ratios of 99.9 and 99.7% against Escherichia coli (Gram-negative) and Bacillus subtilis (Gram-positive), respectively. In addition, PMETM exhibited excellent resistance to Aspergillus niger (fungal) contamination for more than 30 days. Cytotoxicity assays indicated that PMETM was a noncytotoxic material. These results suggested that the insertion of menthoxytriazine in the PET backbone was a promising strategy to confer antimicrobial properties to PET.

A hemicyanine fluorescent probe with intramolecular charge transfer (ICT) mechanism for highly sensitive and selective detection of acidic pH and its application in living cells.

Intracellular pH (pHi) plays an essential role in organelles. Fluorescent probe combined with fluorescence imaging analytical approach has been used for detection pH fluctuation due to high sensitivity and good photostability. Herein, a benzoindole-based colorimetric and naked-eye hemicyanine fluorescent probe 2,3-trimethy-3-[2,4-(dihyoxyl-4-yl)vinyl]-3H-benzo[e]indole (BiDD) was developed in one step. Upon the decreasing of pH, BiDD exhibited strong a pH-dependent characteristic with pKa 4.98 and responded linearly within the pH range of 4.4-6.2. BiDD also showed high sensitivity and selectivity, colorimetric and fluorometric dual-modal response, high photostability, low cytotoxicity as well as good cell membrane permeability. More importantly, the probe was applied to sense and visualize the pH fluctuations in HeLa cells successfully by the fluorescence confocal microscope.

A phenanthro[9,10-d]imidazole-based AIE active fluorescence probe for sequential detection of Ag+/AgNPs and SCN- in water and saliva samples and its application in living cells.

Ag+ and SCN- play extremely important roles in the fields of the physiology and environment. In this work, on the basis of phenanthro[9,10-d]imidazole derivative (DIPIP) which can exhibit the aggregation-induced emission (AIE) properties in aqueous solution, we achieved a sequential on-off-on switch for Ag+ and SCN- with high selectivity and sensitivity. A remarkable fluorescence quenching effect of Ag+ on the probe DIPIP was observed with 1:2 stoichiometry, Subsequently, the fluorescence intensity of in situ generated DIPIP-Ag+ ensemble was easily switched on after the interaction between Ag+ and SCN-, which was attributed to the stronger affinity of SCN- to capture Ag+. In particular, the extreme limits of detection (LOD) for Ag+ and SCN- in standard solutions were as low as to be 74.5 nM and 7.8 nM, respectively. Furthermore, the probe DIPIP and the DIPIP-Ag+ ensemble could be used to detect Ag+ in the real water and SCN- in smoker saliva samples, respectively. In addition, the sequential "on-off-on" fluorescence mode of DIPIP to Ag+ and SCN- were also successfully applied in living HeLa cells.