Antibiotic-free ocular sterilization while suppressing immune response to protect corneal transparency in infectious keratitis treatment.

Clinical guidelines for infectious keratitis treatment require that anti-inflammatory drugs can only be used after infection elimination, which causes irreversible inflammatory damage to the cornea. In this work, photodynamic metal organic frameworks (PCN-224) were used as drug carrier to load Pt NPs with catalase-like activity and anti-inflammatory drug (Dexamethasone, DXMS) for endogenous oxygen generation and reduced corneal damage, respectively. The photodynamic therapy (PDT) effect was greatly enhanced in bacteria elimination and bacterial biofilms removal through catalysis of overexpressed hydrogen peroxide (H2O2, ∼8.0 and 31.0 µM in bacterial solution and biofilms, respectively) into oxygen by Pt NPs. More importantly, the cationic liposome modified PCN-224@Pt@DXMS@Liposomes (PPDL NPs) greatly enhanced the adhesion to negatively charged ocular surface and penetration into corneal barrier and bacterial biofilms. Both in vitro cell viability test and in vivo eye irritation tests proved good biocompatibility of PPDL NPs under 660 nm laser irradiation. Furthermore, PDT of PPDL NPs in rapid bacteria killing was verified through infectious keratitis animal model. The superior bactericidal effect of antibacterial materials could largely replace the bactericidal effect of the immune system. It is worth mentioning that this simultaneous sterilization and anti-inflammation treatment mode is a new exploration against the clinical treatment guidelines.

A water transfer printing method for contact lenses surface 2D MXene modification to resist bacterial infection and inflammation.

Contact lenses (CLs) are prone to adhesion and invasion by pollutants and pathogenic bacteria, leading to infection and inflammatory diseases. However, the functionalization of CL (biological functions such as anti-fouling, antibacterial, and anti-inflammatory) and maintaining its transparency still face great challenges. In this work, as a member of the MXenes family, vanadium carbide (V2C) is modified onto CL via a water transfer printing method after the formation of a tightly arranged uniform film at the water surface under the action of the Marangoni effect. The coating interface is stable owing to the electrostatic forces. The V2C-modified CL (V2C@CL) maintains optical clarity while providing good biocompatibility, strong antioxidant properties, and anti-inflammatory activities. In vitro antibacterial experiments indicate that V2C@CL shows excellent performance in bacterial anti-adhesion, sterilization, and anti-biofilm formation. Last, V2C@CL displays notable advantages of bacteria elimination and inflammation removal in infectious keratitis treatment.

An Antibiotic Nanobomb Constructed from pH-Responsive Chemical Bonds in Metal-Phenolic Network Nanoparticles for Biofilm Eradication and Corneal Ulcer Healing.

In the treatment of refractory corneal ulcers caused by Pseudomonas aeruginosa, antibacterial drugs delivery faces the drawbacks of low permeability and short ocular surface retention time. Hence, novel positively-charged modular nanoparticles (NPs) are developed to load tobramycin (TOB) through a one-step self-assembly method based on metal-phenolic network and Schiff base reaction using 3,4,5-trihydroxybenzaldehyde (THBA), ε-poly-ʟ-lysine (EPL), and Cu2+ as matrix components. In vitro antibacterial test demonstrates that THBA-Cu-TOB NPs exhibit efficient instantaneous sterilization owing to the rapid pH responsiveness to bacterial infections. Notably, only 2.6 µg mL-1 TOP is needed to eradicate P. aeruginosa biofilm in the nano-formed THBA-Cu-TOB owing to the greatly enhanced penetration, which is only 1.6% the concentration of free TOB (160 µg mL-1). In animal experiments, THBA-Cu-TOB NPs show significant advantages in ocular surface retention, corneal permeability, rapid sterilization, and inflammation elimination. Based on molecular biology analysis, the toll-like receptor 4 and nuclear factor kappa B signaling pathways are greatly downregulated as well as the reduction of inflammatory cytokines secretions. Such a simple and modular strategy in constructing nano-drug delivery platform offers a new idea for toxicity reduction, physiological barrier penetration, and intelligent drug delivery.

A Novel "Inside-Out" Intraocular Nanomedicine Delivery Mode for Nanomaterials' Biological Effect Enhanced Choroidal Neovascularization Occlusion and Microenvironment Regulation.

Photodynamic therapy (PDT) is commonly used in choroidal neovascularization (CNV) treatment due to the superior light transmittance of the eye. However, PDT often leads to surrounding tissue damage and further microenvironmental deterioration, including exacerbated hypoxia, inflammation, and secondary neovascularization. In this work, Pt nanoparticles (NPs) and Au NPs decorated zeolitic imidazolate framework-8 nanoplatform is developed to load indocyanine green for precise PDT and microenvironment amelioration, which can penetrate the internal limiting membrane through Müller cells endocytosis and target to CNV by surface-grafted cyclo(Arg-Gly-Asp-d-Phe-Lys) after intravitreal injection. The excessive H2 O2 in the CNV microenvironment is catalyzed by catalase-like Pt NPs for hypoxia relief and enhanced PDT occlusion of neovascular. Meanwhile, Au NPs show significant anti-inflammatory and anti-angiogenesis properties in regulating macrophages and blocking vascular endothelial growth factor (VEGF). Compared with verteporfin treatment, the mRNA expressions of hypoxia-inducible factor-1α and VEGF in the nanoplatform group are downregulated by 90.2% and 81.7%, respectively. Therefore, the nanoplatform realizes a comprehensive CNV treatment effect based on the high drug loading capacity and biosafety. The CNV treatment mode developed in this work provides a valuable reference for treating other diseases with similar physiological barriers that limit drug delivery and similar microenvironment.

Instant Adhesion of Amyloid-like Nanofilms with Wet Surfaces.

The adhesion and modification of wet surfaces by an interfacial adlayer remain a key challenge in chemistry and materials science. Herein, we report a transparent and biocompatible amyloid-like nanofilm that breaks through the hydration layer of a wet surface and achieves strong adhesion with a hydrogel/tissue surface within 2 s. This process is facilitated by fast amyloid-like protein aggregation at the air/water interface and the resultant exposure of hydrophobic groups. The resultant protein nanofilm adhered to a hydrogel surface presents an adhesion strength that is 20 times higher than the maximum friction force between the upper eyelid and eyeball. In addition, the nanofilm exhibits controllable tunability to encapsulate and release functional molecules without significant activity loss. As a result, therapeutic contact lenses (CLs) could be fabricated by adhering the functionalized nanofilm (carrying drug) on the CL surface. These therapeutic CLs display excellent therapeutic efficacy, showing an increase in cyclosporin A (CsA) bioavailability of at least 82% when compared to the commercial pharmacologic treatment for dry eye syndrome. Thus, this work underlines the finding that the bioinspired amyloid-like aggregation of proteins at interfaces drives instant adhesion onto a wet surface, enabling the active loading and controllable release of functional building blocks.

pH-Activatable Organic Nanoparticles for Efficient Low-Temperature Photothermal Therapy of Ocular Bacterial Infection.

Low-temperature photothermal therapy (PTT) systems constructed by integrating organic photothermal agents with other bactericidal components that initiate bacterial apoptosis at low hyperthermia possess a promising prospect. However, these multicomponent low-temperature PTT nanoplatforms have drawbacks in terms of the tedious construction process, suboptimal synergy effect of diverse antibacterial therapies, and high laser dose needed, compromising their biosafety in ocular bacterial infection treatment. Herein, a mild PTT nanotherapeutic platform is formulated via the self-assembly of a pH-responsive phenothiazinium dye. These organic nanoparticles with photothermal conversion efficiency up to 84.5% necessitate only an ultralow light dose of 36 J/cm2 to achieve efficient low-temperature photothermal bacterial inhibition at pH 5.5 under 650 nm laser irradiation. In addition, this intelligent mild photothermal nanoplatform undergoes negative to positive charge reversion in acid biofilms, exhibiting good penetration and highly efficient elimination of drug-resistant E. coli biofilms under photoirradiation. Further in vivo animal tests demonstrated efficient bacterial elimination and inflammatory mitigation as well as superior biocompatibility and biosafety of the photothermal nanoparticles in ocular bacterial infection treatment. Overall, this efficient single-component mild PTT system featuring simple construction processes holds great potential for wide application and clinical transformation.

Cyanobacteria-based self-oxygenated photodynamic therapy for anaerobic infection treatment and tissue repair.

Photodynamic therapy (PDT) is an important technique to deal with drug-resistant bacterial infections in the post-antibiotic era. However, the hypoxic environment in intractable infections such as refractory keratitis and periodontitis, makes PDT more difficult. In this work, spontaneous oxygen-producing cyanobacteria were used as the carrier of photosensitizer (Ce6), and ultrasmall Cu5.4O nanoparticles (Cu5.4O USNPs) with catalase activity for infection and inflammation elimination and rapid tissue repair (CeCycn-Cu5.4O). The loading of Ce6 and Cu5.4O USNPs onto cyanobacteria surface were confirmed by transmission electron microscopy, nano particle size analyzer, scanning electron microscopy. In vitro sterilization and biofilm removal experiments demonstrated that the restriction of hypoxic environment to PDT was significantly alleviated due to the oxygen production of cyanobacteria. Under laser irradiation, the close transfer of energy photons to oxygen produced by cyanobacteria reduced more than 90% of Ce6 dosages (660 nm, 200 mW/cm2, 2 min). It is worth mentioning that both rapid sterilization through PDT and long-term oxidized free radicals elimination were achieved by adjusting the ratio of Ce6 and Cu5.4O USNPs. Both periodontitis and refractory keratitis animal models proved the excellent self-oxygenation enhanced antibacterial property and promotion of tissue repair.

Reversible antibiotic loading and pH-responsive release from polymer brushes on contact lenses for therapy and prevention of corneal infections.

Corneal infection is an important cause of corneal damage and vision loss. In this work, polyhydroxy antibiotics were grafted onto polymer brush-modified contact lenses through dynamic chemical bonds between polyphenolic hydroxyls and phenylboronic acid. Both in vitro and in vivo antibacterial tests demonstrated great promise in the prevention of bacterial keratitis, which could be attributed to the enhanced retention time and drug bioavailability.

Synergistic Chemotherapy and Photodynamic Therapy of Endophthalmitis Mediated by Zeolitic Imidazolate Framework-Based Drug Delivery Systems.

Endophthalmitis, derived from the infections of pathogens, is a common complication during the use of ophthalmology-related biomaterials and after ophthalmic surgery. Herein, aiming at efficient photodynamic therapy (PDT) of bacterial infections and biofilm eradication of endophthalmitis, a pH-responsive zeolitic imidazolate framework-8-polyacrylic acid (ZIF-8-PAA) material is constructed for bacterial infection-targeted delivery of ammonium methylbenzene blue (MB), a broad-spectrum photosensitizer antibacterial agent. Polyacrylic acid (PAA) is incorporated into the system to achieve higher pH responsiveness and better drug loading capacity. MB-loaded ZIF-8-PAA nanoparticles are modified with AgNO3 /dopamine for in situ reduction of AgNO3 to silver nanoparticles (AgNPs), followed by a secondary modification with vancomycin/NH2 -polyethylene glycol (Van/NH2 -PEG), leading to the formation of a composite nanomaterial, ZIF-8-PAA-MB@AgNPs@Van-PEG. Dynamic light scattering, transmission electron microscopy, and UV-vis spectral analysis are used to explore the nanoparticles synthesis, drug loading and release, and related material properties. In terms of biological performance, in vitro antibacterial studies against three kinds of bacteria, i.e., Escherichia coli, Staphylococcus aureus, and methicillin-resistant S. aureus, suggest an obvious superiority of PDT/AgNPs to any single strategy. Both in vitro retinal pigment epithelium cellular biocompatibility experiments and in vivo mice endophthalmitis models verify the biocompatibility and antibacterial function of the composite nanomaterials.

Photosensitizer-Loaded Multifunctional Chitosan Nanoparticles for Simultaneous in Situ Imaging, Highly Efficient Bacterial Biofilm Eradication, and Tumor Ablation.

In recent decades, bacterial and viral infections and chronic inflammatory response have emerged as important causes of cancer. Also, infections remain a significant cause of morbidity and mortality in cancer patients. In this work, carboxymethyl chitosan nanoparticles (CMC NPs) were synthesized in a facile and green way and further combined with ammonium methylbenzene blue (MB) as a cross-linking agent as well as a fluorescent molecule and a photosensitizer for self-imaging photodynamic therapy (PDT). The obtained CMC-MB NPs exhibited an apparent pH-responsive release behavior of MB, which was released for a prolonged period in a simulated physiological environment (pH 7.4) for more than 15 days and the time reduced to only 3.5 h in acidic conditions (pH 5.5). When irradiated by a 650 nm laser at 202 mW/cm2 for 5 min, the CMC-MB NPs showed efficient bactericidal and biofilm eradication properties as well as suppression of tumor cell growth in a similar acidified microenvironment. Furthermore, in an in vivo rabbit wound bacterial infection model, the rapid sterilization of CMC-MB NPs played a crucial role in bacterial infections, inflammation inhibition, and wound healing. As a PDT treatment against cancer, the CMC-MB NPs also exhibited an efficient antitumor therapeutic effect in a subcutaneous tumor mice model.