Near infrared II excitation nanoplatform for photothermal/chemodynamic/antibiotic synergistic therapy combating bacterial biofilm infections.

Drug-resistant bacterial biofilm infections (BBIs) are refractory to elimination. Near-infrared-II photothermal therapy (NIR-II PTT) and chemodynamic therapy (CDT) are emerging antibiofilm approaches because of the heavy damage they inflict upon bacterial membrane structures and minimal drug-resistance. Hence, synergistic NIR-II PTT and CDT hold great promise for enhancing the therapeutic efficacy of BBIs. Herein, we propose a biofilm microenvironment (BME)-responsive nanoplatform, BTFB@Fe@Van, for use in the synergistic NIR-II PTT/CDT/antibiotic treatment of BBIs. BTFB@Fe@Van was prepared through the self-assembly of phenylboronic acid (PBA)-modified small-molecule BTFB, vancomycin, and the CDT catalyst Fe2+ ions in DSPE-PEG2000. Vancomycin was conjugated with BTFB through a pH-sensitive PBA-diol interaction, while the Fe2+ ions were bonded to the sulfur and nitrogen atoms of BTFB. The PBA-diol bonds decomposed in the acidic BME, simultaneously freeing the vancomycin and Fe2+ irons. Subsequently, the catalytic product hydroxyl radical was generated by the Fe2+ ions in the oxidative BME overexpressed with H2O2. Moreover, under 1064 nm laser, BTFB@Fe@Van exhibited outstanding hyperthermia and accelerated the release rate of vancomycin and the efficacy of CDT. Furthermore, the BTFB@Fe@Van nanoplatform enabled the precise NIR-II imaging of the infected sites. Both in-vitro and in-vivo experiments demonstrated that BTFB@Fe@Van possesses a synergistic NIR-II PTT/CDT/antibiotic mechanism against BBIs.

Increasing Molecular Planarity through Donor/Side-Chain Engineering for Improved NIR-IIa Fluorescence Imaging and NIR-II Photothermal Therapy under 1064†nm.

Developing conjugated small molecules (CSM) with intense NIR-II (1000-1700 nm) absorption for phototheranostic is highly desirable but remains a tremendous challenge due to a lack of reliable design guidelines. This study reports a high-performance NIR-II CSM for phototheranostic by tailoring molecular planarity. A series of CSM show bathochromic absorption extended to the NIR-II region upon the increasing thiophene number, but an excessive number of thiophene results in decreased NIR-IIa (1300-1400 nm) brightness and photothermal effects. Further introduction of terminal nonconjugated alkyl chain can enhance NIR-II absorption coefficient, NIR-IIa brightness, and photothermal effects. Mechanism studies ascribe this overall enhancement to molecular planarity stemming from the collective contribution of donor/side-chain engineering. This finding directs the design of NIR-II CSM by rational manipulating molecular planarity to perform 1064 nm mediated phototheranostic at high efficiency.

Deep Tumor Penetrating Gold Nano-Adjuvant for NIR-II-Triggered In Situ Tumor Vaccination.

Local tumor photothermal treatment with the near-infrared light at the second window (NIR-II) is a promising strategy in triggering the in situ tumor vaccination (ISTV) for cancer therapy. However, limited penetration of photothermal agents within tumors seriously limits their spatial effect in generating sufficient tumor-associated antigens, a key factor to the success of ISTV. In this study, a nano-adjuvant system is fabricated based on the NIR-II-absorbable gold nanostars decorated with hyaluronidases and immunostimulatory oligodeoxynucleotides CpG for ISTV. The nano-adjuvant displays a deep tumor penetration capacity via loosening the dense extracellular matrix of tumors. Upon NIR-II light irradiation, the nano-adjuvant significantly inhibits the tumor growth, induces a cascade of immune responses, generates an obvious adaptive immunity against the re-challenged cancers, boosts the abscopal effect, and completely inhibits the pulmonary metastases. The study highlights an advanced nano-adjuvant formulation featuring deep tumor penetration for NIR-II-triggered ISTV.

Near-infrared excitation/emission microscopy with lanthanide-based nanoparticles.

Near-infrared optical imaging offers some advantages over conventional imaging, such as deeper tissue penetration, low or no autofluorescence, and reduced tissue scattering. Lanthanide-doped nanoparticles (LnNPs) have become a trend in the field of photoactive nanomaterials for optical imaging due to their unique optical features and because they can use NIR light as excitation and/or emission light. This review is focused on NaREF4 NPs and offers an overview of the state-of-the-art investigation in their use as luminophores in optical microscopy, time-resolved imaging, and super-resolution nanoscopy based on, or applied to, LnNPs. Secondly, whenever LnNPs are combined with other nanomaterial or nanoparticle to afford nanohybrids, the characterization of their physical and chemical properties is of current interest. In this context, the latest trends in optical microscopy and their future perspectives are discussed.

High-Performance Hybrid Phototheranostics for NIR-IIb Fluorescence Imaging and NIR-II-Excitable Photothermal Therapy.

Photothermal therapy operated in the second near-infrared (NIR-II, 1000-1700 nm) window and fluorescence imaging in the NIR-IIb (1500-1700 nm) region have become the most promising techniques in phototheranostics. Their combination enables simultaneous high-resolution optical imaging and deep-penetrating phototherapy, which is essential for high-performance phototheranostics. Herein, carboxyl-functionalized small organic photothermal molecules (Se-TC) and multi-layered NIR-IIb emissive rare-earth-doped nanoparticles (NaYF4:Yb,Er,Ce@NaYF4:Yb,Nd@NaYF4, RENP) were rationally designed and successfully synthesized. Then, high-performance hybrid phototheranostic nanoagents (Se-TC@RENP@F) were easily constructed through the coordination between Se-TC and RENP and followed by subsequent F127 encapsulation. The carboxyl groups of Se-TC can offer strong binding affinity towards rare-earth-doped nanoparticles, which help improving the stability of Se-TC@RENP@F. The multilayered structure of RENP largely enhance the NIR-IIb emission under 808 nm excitation. The obtained Se-TC@RENP@F exhibited high 1064 nm absorption (extinction coefficient: 24.7 L g-1 cm-1), large photothermal conversion efficiency (PCE, 36.9%), good NIR-IIb emission (peak: 1545 nm), as well as great photostability. Upon 1064 nm laser irradiation, high hyperthermia can be achieved to kill tumor cells efficiently. In addition, based on the excellent NIR-IIb emission of Se-TC@RENP@F, in vivo angiography and tumor detection can be realized. This work provides a distinguished paradigm for NIR-IIb-imaging-guided NIR-II photothermal therapy and establishes an artful strategy for high-performance phototheranostics.

Iron-based and BRD4-downregulated strategy for amplified ferroptosis based on pH-sensitive/NIR-II-boosted nano-matchbox.

Ferroptosis (FPT), a novel form of programmed cell death, is characterized by overwhelming iron/reactive oxygen species (ROS)-dependent accumulation of lipid peroxidation (LPO). However, the insufficiency of endogenous iron and ROS level limited the FPT therapeutic efficacy to a large extent. To overcome this obstacle, the bromodomain-containing protein 4 (BRD4)-inhibitor (+)-JQ1 (JQ1) and iron-supplement ferric ammonium citrate (FAC)-loaded gold nanorods (GNRs) are encapsulated into the zeolitic imidazolate framework-8 (ZIF-8) to form matchbox-like GNRs@JF/ZIF-8 for the amplified FPT therapy. The existence of matchbox (ZIF-8) is stable in physiologically neutral conditions but degradable in acidic environment, which could prevent the loaded agents from prematurely reacting. Moreover, GNRs as the drug-carriers induce the photothermal therapy (PTT) effect under the irradiation of near-infrared II (NIR-II) light owing to the absorption by localized surface plasmon resonance (LSPR), while the hyperthermia also boosts the JQ1 and FAC releasing in the tumor microenvironment (TME). On one hand, the FAC-induced Fenton/Fenton-like reactions in TME can simultaneously generate iron (Fe3+/Fe2+) and ROS to initiate the FPT treatment by LPO elevation. On the other hand, JQ1 as a small molecule inhibitor of BRD4 protein can amplify FPT through downregulating the expression of glutathione peroxidase 4 (GPX4), thus inhibiting the ROS elimination and leading to the LPO accumulation. Both in vitro and in vivo studies reveal that this pH-sensitive nano-matchbox achieves obvious suppression of tumor growth with good biosafety and biocompatibility. As a result, our study points out a PTT combined iron-based/BRD4-downregulated strategy for amplified ferrotherapy which also opens the door of future exploitation of ferrotherapy systems.

Pt Decorated Ti3C2Tx MXene with NIR-II Light Amplified Nanozyme Catalytic Activity for Efficient Phototheranostics.

The clinical application of photothermal therapy (PTT) is severely limited by the tissue penetration depth of excitation light, and enzyme therapy is hampered by its low therapeutic efficiency. As a two-dimensional ultrathin nanosheet with high absorbance in the near-infrared-II (NIR-II) region, the titanium carbide (Ti3C2) nanosheet can be used as a substrate to anchor functional components, like nanozymes and nanodrugs. Here, we decorate Pt artificial nanozymes on the Ti3C2 nanosheets to synthesize Ti-based MXene nanocomposites (Ti3C2Tx-Pt-PEG). In the tumor microenvironment, the Pt nanoparticles exhibit peroxidase-like (POD-like) activity, which can in situ catalyze hydrogen peroxide to generate hydroxyl radicals (•OH) to induce cell apoptosis and necrosis. Meanwhile, the composite shows a desirable photothermal effect upon NIR-II light irradiation with a low power density (0.75 W cm-2). Especially, the POD-like activity is significantly enhanced by the elevated temperature arising from the photothermal effect of Ti3C2Tx. Therefore, satisfactory synergistic PTT/enzyme therapy has been accomplished, accompanied by an applicable photoacoustic imaging capability to monitor and guide the therapeutic process. This work may provide an approach for hyperthermia-amplified nanozyme catalytic therapy, especially based on metal catalysts and MXene nanocomposites.

Bioactive NIR-II Light-Responsive Shape Memory Composite Based on Cuprorivaite Nanosheets for Endometrial Regeneration.

Intrauterine adhesions (IUAs) caused by mechanical damage or infection increase the risk of infertility in women. Although numerous physical barriers such as balloon or hydrogel are developed for the prevention of IUAs, the therapeutic efficacy is barely satisfactory due to limited endometrial healing, which may lead to recurrence. Herein, a second near-infrared (NIR-II) light-responsive shape memory composite based on the combination of cuprorivaite (CaCuSi4 O10 ) nanosheets (CUP NSs) as photothermal conversion agents and polymer poly(d,l-lactide-co-trimethylene carbonate) (PT) as shape memory building blocks is developed. The as-prepared CUP/PT composite possesses excellent shape memory performance under NIR-II light, and the improved operational feasibility as an antiadhesion barrier for the treatment of IUAs. Moreover, the released ions (Cu, Si) can stimulate the endometrial regeneration due to the angiogenic bioactivity. This study provides a new strategy to prevent IUA and restore the injured endometrium relied on shape memory composite with enhanced tissues reconstruction ability.

All-In-One Second Near-Infrared Light-Responsive Drug Delivery System for Synergistic Chemo-Photothermal Therapy.

Light-responsive nanocarrier-based drug delivery systems (NDDSs), due to their unique advantages such as safety, minimal cross-reaction, and spatiotemporal precision, have received wide attention. Notably, second near-infrared (NIR-II) light, which has a high penetration depth for manipulating NDDSs to release drugs, is in high demand. Herein, polyethylene glycol (PEG)-modified hollow CuxS nanoparticles (NPs) are developed as an all-in-one NIR-II light-responsive NDDS for synergistic chemo-photothermal therapy. First, CuxS-PEG NPs were prepared under mild conditions by using Cu2O NPs as sacrificial templates. The morphology, photothermal effect, drug loading/releasing abilities, and synergistic chemo-photothermal therapy of CuxS-PEG NPs have been investigated. The CuxS-PEG NPs with hollow structures showed a high drug loading capacity (∼255 µg Dox per mg of CuxS NPs) and stimuli-responsive drug release triggered by NIR-II laser irradiation. The synergistic chemo-photothermal therapy based on the Dox/CuxS-PEG NPs showed 98.5% tumor elimination. Our study emphasizes the great potential of CuxS-PEG NPs as an all-in-one NIR-II light-responsive NDDS for applications in biomedicine.

Conjugated Polymer-Ferrocence Nanoparticle as an NIR-II Light Powered Nanoamplifier to Enhance Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a promising therapeutic modality with transition metal ions and endogenous H2O2 as reagents, but its efficiency is impaired by low endogenous H2O2 levels and nonregeneration of metal ions. Most intracellular H2O2 supplement strategies use oxidases and are intensively dependent on oxygen participation. The hypoxia microenvironments of solid tumors weaken their performance. Here, we develop a near-infrared II light powered nanoamplifier to improve the local oxygen level and to enhance CDT. The nanoamplifier CPNP-Fc/Pt consists of ferrocene (Fc)- and cisplatin prodrug (Pt(IV))-modified conjugated polymer nanoparticles (CPNPs). CPNP has a donor-acceptor structure and demonstrates a good photothermal effect under 1064 nm light irradiation, which accelerates blood flow and efficiently elevates the local oxygen content. In response to intracellular glutathione, Pt(II) is released from CPNP-Fc/Pt and triggers enzymatic cascade reactions with nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and superoxide dismutase to convert oxygen into H2O2. The enhanced oxygen level results in efficient intracellular H2O2 supply. Fc is reacted with H2O2 and converted to Fc+ via the Fenton reaction, with the generation of hydroxyl radicals for CDT. Unlike free metal ions, the Fe(III) in Fc+ is reduced to Fe(II) by intracellular NAD(P)H, which achieves the regeneration of Fc. The sufficient intracellular H2O2 supply and efficient Fc regeneration effectively enhance the Fenton reaction and demonstrate good in vivo CDT results with tumor growth suppression. This design offers a promising strategy to enhance CDT efficiency in the hypoxia microenvironment of solid tumors.

Rough Carbon-Iron Oxide Nanohybrids for Near-Infrared-II Light-Responsive Synergistic Antibacterial Therapy.

Infections caused by multidrug resistant bacteria are still a serious threat to human health. It is of great significance to explore effective alternative antibacterial strategies. Herein, carbon-iron oxide nanohybrids with rough surfaces (RCF) are developed for NIR-II light-responsive synergistic antibacterial therapy. RCF with excellent photothermal property and peroxidase-like activity could realize synergistic photothermal therapy (PTT)/chemodynamic therapy (CDT) in the NIR-II biowindow with improved penetration depth and low power density. More importantly, RCF with rough surfaces shows increased bacterial adhesion, thereby benefiting both CDT and PTT through effective interaction between RCF and bacteria. In vitro antibacterial experiments demonstrate a broad-spectrum synergistic antibacterial effect of RCF against Gram-negative Escherichia coli (E. coli), Gram-positive Staphylococcus aureus (S. aureus), and methicillin-resistant Staphylococcus aureus (MRSA). In addition, satisfactory biocompatibility makes RCF a promising antibacterial agent. Notably, the synergistic antibacterial performances in vivo could be achieved employing the rat wound model with MRSA infection. The current study proposes a facile strategy to construct antibacterial agents for practical antibacterial applications by the rational design of both composition and morphology. RCF with low power density NIR-II light responsive synergistic activity holds great potential in the effective treatment of drug-resistant bacterial infections.

NIR-II reinforced intracellular cyclic reaction to enhance chemodynamic therapy with abundant H2O2 supply.

Chemodynamic therapy (CDT) is an ideal therapeutic modality with endogenous H2O2 as stimulus. Most intracellular H2O2 supplement strategies for improving CDT efficiency are strongly rely on oxygen participation, and the hypoxia tumor microenvironment impairs their performance. Here we develop a self-assembled metal-organic coordinated nanoparticle Cu-OCNP/Lap with NIR-II reinforced intracellular cyclic reaction to enhance CDT efficiency. Cu-OCNP/Lap is synthesized using Cu2+ as nodes and 1,4,5,8-tetrahydroxyanthraquinone (THQ) and banoxantrone dihydrochloride (AQ4N) as ligands, with ß-lapachone (ß-Lap) loading to conduct intracellular cyclic reaction. Cu-OCNP/Lap has good photothermal effect at NIR-II window, and the corresponding local temperature increase speeds blood flow and supplies sufficient oxygen at tumor site to reinforce ß-Lap cyclic reaction with abundant H2O2 generation. Cu+ is released from Cu-OCNP/Lap in response to glutathione (GSH) and triggers CDT. Sufficient intracellular H2O2 supply enhances CDT effect and demonstrates good suppressions for tumor growth. This design offers a promising strategy to enhance CDT efficiency.

Site-Selective Photosynthesis of Ag-AgCl@Au Nanomushrooms for NIR-II Light-Driven O2- and O2•--Evolving Synergistic Photothermal Therapy against Deep Hypoxic Tumors.

Light-driven endogenous water oxidation has been considered as an attractive and desirable way to obtain O2 and reactive oxygen species (ROS) in the hypoxic tumor microenvironment. However, the use of a second near-infrared (NIR-II) light to achieve endogenous H2O oxidation to alleviate tumor hypoxia and realize deep hypoxic tumor phototherapy is still a challenge. Herein, novel plasmonic Ag-AgCl@Au core-shell nanomushrooms (NMs) were synthesized by the selective photodeposition of plasmonic Au at the bulge sites of the Ag-AgCl nanocubes (NCs) under visible light irradiation. Upon NIR-II light irradiation, the resulting Ag-AgCl@Au NMs could oxidize endogenous H2O to produce O2 to alleviate tumor hypoxia. Almost synchronously, O2 could react with electrons on the conduction band of the AgCl core to generate superoxide radicals (O2•-)for photodynamic therapy. Moreover, Ag-AgCl@Au NMs with an excellent photothermal performance could further promote the phototherapy effect. In vitro and in vivo experimental results show that the resulting Ag-AgCl@Au NMs could significantly improve tumor hypoxia and enhance phototherapy against a hypoxic tumor. The present study provides a new strategy to design H2O-activatable, O2- and ROS-evolving NIR II light-response nanoagents for the highly efficient and synergistic treatment of deep O2-deprived tumor tissue.

Photothermal Therapy via NIR II Light Irradiation Enhances DNA Damage and Endoplasmic Reticulum Stress for Efficient Chemotherapy.

Ovarian cancer has the highest death rate in gynecologic tumors and the main therapy for patients with advanced is chemotherapy based on cisplatin. Additionally, hyperthermic intraperitoneal has been used in clinic to obtain better efficacy for patients. Hence, combined photothermal therapy with platinum drugs in a new delivery system might bring new hope for ovarian cancer. A reduction sensitive polymer encapsulating a Pt (IV) prodrug and a near infrared II (NIR II) photothermal agent IR1048 to form nanoparticles were reported to enhance the efficacy of ovarian cancer treatment. At the same time, endoplasmic reticulum stress indicates an imbalance in proteostasis which probably caused by extrinsic stress such as chemotherapy and the temperature changed. The efficacy of nanoparticles containing Pt (IV) and IR1048 under NIR II light might be caused via increased DNA damage and endoplasmic reticulum (ER) stress.

Rationally designed dual-plasmonic gold nanorod@cuprous selenide hybrid heterostructures by regioselective overgrowth for in vivo photothermal tumor ablation in the second near-infrared biowindow.

NIR-II plasmonic materials offer multiple functionalities for in vivo biomedical applications, such as photothermal tumor ablation, surface-enhanced Raman scattering biosensing, photoacoustic imaging, and drug carriers. However, integration of noble metals and plasmonic semiconductors is greatly challenging because of the large lattice-mismatch. This study reports the regioselective overgrowth of Cu2-xSe on gold nanorods (GNRs) for preparation of dual-plasmonic GNR@Cu2-xSe hybrid heterostructures with tunable NIR-II plasmon resonance absorption for in vivo photothermal tumor ablation. Methods: The regioselective deposition of amorphous Se and its subsequent conversion into Cu2-xSe on the GNRs are performed by altering capping agents to produce the GNR@Cu2-xSe heterostructures of various morphologies. Their photothermal performances for NIR-II photothermal tumor ablation are evaluated both in vitro and in vivo. Results: We find that the lateral one- and two-side deposition, conformal core-shell coating and island growth of Cu2-xSe on the GNRs can be achieved using different capping agents. The Cu2-xSe domain size in these hybrids can be effectively adjusted by the SeO2 concentration, thereby tuning the NIR-II plasmon bands. A photothermal conversion efficiency up to 58-85% and superior photostability of these dual-plasmonic hybrids can be achieved under the NIR-II laser. Results also show that the photothermal conversion efficiency is dependent on the proportion of optical absorption converted into heat; however, the temperature rise is tightly related to the concentration of their constituents. The excellent NIR-II photothermal effect is further verified in the following in vitro and in vivo experiments. Conclusions: This study achieves one-side or two-side deposition, conformal core-shell coating, and island deposition of Cu2-xSe on GNRs for GNR@Cu2-xSe heterostructures with NIR-II plasmonic absorption, and further demonstrates their excellent NIR-II photothermal tumor ablation in vivo. This study provides a promising strategy for the rational design of NIR-II dual-plasmonic heterostructures and highlights their therapeutic in vivo potential.