Bacteria-based cascade in situ near-infrared nano-optogenetically induced photothermal tumor therapy.

Rationale: Optogenetically engineered facultative anaerobic bacteria exhibit a favorable tendency to colonize at solid tumor sites and spatiotemporally-programmable therapeutics release abilities, attracting extensive attention in precision tumor therapy. However, their therapeutic efficacy is moderate. Conventional photothermal agents with high tumor ablation capabilities exhibit low tumor targeting efficiency, resulting in significant off-target side effects. The combination of optogenetics and photothermal therapy may offer both tumor-targeting and excellent tumor-elimination capabilities, which unfortunately has rarely been investigated. Herein, we construct a bacteria-based cascade near-infrared optogentical-photothermal system (EcNαHL-UCNPs) for enhanced tumor therapy. Methods: EcNαHL-UCNPs consists of an optogenetically engineered Escherichia coli Nissle 1917 (EcN) conjugated with lanthanide-doped upconversion nanoparticles (UCNPs), which are capable of locally secreting α-hemolysin (αHL), a pore-forming protein, in responsive to NIR irradiation. Anti-tumor effects of EcNαHL-UCNPs were determined in both H22 and 4T1 tumors. Results: The αHL not only eliminates tumor cells, but more importantly disrupts endothelium to form thrombosis as an in situ photothermal agent in tumors. The in situ formed thrombosis significantly potentiates the photothermic ablation of H22 tumors upon subsequent NIR light irradiation. Besides, αHL secreted by EcNαHL-UCNPs under NIR light irradiation not only inhibits 4T1 tumor growth, but also suppresses metastasis of 4T1 tumor via inducing the immune response. Conclusion: Our studies highlight bacteria-based cascade optogenetical-photothermal system for precise and effective tumor therapy.

Laser enhanced photothermal effect of silver nanoparticles synthesized by chemical and green method on Gram-positive and Gram-negative bacteria.

PURPOSE: The antibacterial properties of silver nanoparticles (AgNPs) are extensively identified. In large quantities, they might be harmful. So many fields of nanotechnology have shown a great deal of interest in the development of an environmentally friendly, efficient method for synthesizing metal nanoparticles. Because of its antibacterial and antifungal properties toward a wide range of microbes, chitosan silver nanoparticles (AgNPs@Cs) constitute a newly developing class of bio-nanostructured hybrid materials. Furthermore, the use of photothermal therapy (PTT) has been suggested as a means of elimination of germs. These light-stimulated treatments are minimally invasive and have a few side effects. In the present work, the antibacterial effect of AgNPs at low concentrations; prepared by chemical and green methods as antimicrobial and photothermal agents in photothermal therapy; with laser irradiation were explored as combined treatment against MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae. METHODS: Silver nanoparticles were produced in two ways. First, by sodium borohydrides, second, by chitosan (as a natural eco-friendly reducing, and capping agent). The nanostructure of AgNPs and AgNPs@Cs was confirmed by UV-visible spectrometer, transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIRs), and direct light scattering (DLS). The antibacterial activity of the prepared nanoparticles and the laser irradiation was tested against three bacterial species of zoonotic importance; MRSA, Pseudomonas aeruginosa, and Klebsiella pneumoniae; and was evaluated by measuring their minimum inhibitory concentrations (MIC). RESULTS: Silver nanoparticles produced by the two methods had spherical shapes with nearly the same particle size. The analysis of DLS showed that AgNPs were very stable with zeta potential - 28.8 mv, and 47.7 mv by chemical and chitosan synthesis, respectively. Furthermore, AgNPs@Cs showed higher antibacterial activity toward the tested bacterial species than AgNPs by chemical method. Additionally, the bacterial viability using photothermal laser therapy was reduced compared to laser and AgNPs alone. The bactericidal activities were higher when laser diode was coupled with AgNPs@Cs than by chemical reduction. CONCLUSION: The laser combined treatment had a higher antimicrobial effect than AgNPs alone or laser irradiation alone.

Aggregation-Induced Emission-Active Organic Nanoagent with High Photothermal Conversion Efficiency for Near-Infrared Imaging-Guided Tumor Photothermal Therapy.

Photothermal therapy (PTT) provides a great prospect for noninvasive cancer therapy. However, it is still highly challenging to construct photothermal agents (PTAs) with the desired performances for imaging-guided PTT applications. Herein, a D-A-D-type naphthalene diamine (NDI)-based photothermal nano-PTAs NDS-BPN NP with near-infrared region (NIR) emission at 822 nm, aggregation-induced emission (AIE), high photothermal conversion efficiency (55.05%), and excellent photothermal stability is successfully designed and prepared through a simple two-step engineering method by using a new AIE molecule NDS-BPN and DSPE-PEG2000 as precursors. The prepared PTT nanoagents NDS-BPN NPs have been further applied for efficient photothermal ablation of cancer cells in vitro and also achieved the NIR fluorescent image-guided PTT tumor therapy in vivo with satisfactory results. We believe that this work provides an attractive NIR AIE NDI-based nano-PTA for the phototherapy of tumors as well as develops the construction strategy of NDI molecular-based photothermal nanoagents with desired performances for imaging-guided PTT.

Croconaine-based NIR-II fluorescence imaging-guided tumor photothermal therapy induces long-term antitumor immune memory.

Photothermal therapy (PTT) for cancers guided by optical imaging has recently shown great potential for precise diagnosis and efficient therapy. The second near-infrared window (NIR-II, 1000-1700 nm) fluorescence imaging (FLI) is highly desirable owing to its good spatial and temporal resolution, deep tissue penetration, and negligible tissue toxicity. Organic small molecules are attractive as imaging and treatment agents in biomedical research because of their low toxicity, fast clearance rate, diverse structures, ease of modification, and excellent biocompatibility. Various organic small molecules have been investigated for biomedical applications. However, there are few reports on the use of croconaine dyes (CRs), especially NIR-II emission CRs. To our knowledge, there have been no prior reports of NIR-II emissive small organic photothermal agents (SOPTAs) based on CRs. Herein, we report a croconaine dye (CR-TPE-T)-based nanoparticle (CR NP) with absorption and fluorescence emission in the NIR-I and NIR-II windows, respectively. The CR NPs exhibited intense NIR absorption, outstanding photothermal properties, and good biological compatibility. In vivo studies showed that CR NPs not only achieved real-time, noninvasive NIR-II FLI of tumors, but also induced significant tumor ablation with laser irradiation guided by imaging, without apparent side effects, and promoted the formation of antitumor immune memory in a colorectal cancer model. In addition, the CR NPs displayed efficient inhibition of breast tumor growth, improved longevity of mice and triggered efficient systemic immune responses, which further inhibited tumor metastasis to the lungs. Our study demonstrates the great potential of CRs as therapeutic agents in the NIR-II region for cancer diagnosis.

Design of Biopolymer-Coated Gold Nanorods as Biorelevant Photothermal Agents.

Gold nanorods (AuNRs) are emerging metallic nanoparticles utilized to generate heat for photothermal therapy (PTT) in cancer. The tunable plasmonic properties of AuNRs make them a remarkable candidate for hyperthermia. However, the cytotoxicity of AuNRs limits its biological applicability due to the existence of cetyltrimethylammonium bromide (CTAB) on the surface as a common surfactant. In this study, AuNRs are synthesized by seed-mediated growth and then the optical properties are optimized by altering AgNO3 concentration. Afterward, CTAB is replaced with biopolymers which are BSA:Dextran and BSA:Guar Gum conjugates resulting in enhanced cellular viability, enabling to use of them as biologically relevant photothermal agents. The biocompatibility of AuNRs is improved to utilize them at high concentrations for laser studies, in which similar heat generation success of CTAB- and biopolymer-coated AuNRs are shown for potential PTT applications. CTAB and biopolymer-coated AuNRs in concentrations of 0.5 and 1 mg mL-1 are irradiated under NIR light at 808 nm laser at 0.5, 0.75, and 1 W cm-2 for 300 s. The biopolymer-coated gold nanorods with different coatings preserve photothermal properties while reducing the cytotoxicity effects of CTAB and thus they are promising photothermal agents for potential PTT.

Making the Brightest Ones Dim: Maximizing the Photothermal Conversion Efficiency of BODIPY-Based Photothermal Agents.

The successful implementation of photothermal therapy (PTT) in cancer treatment hinges on the development of highly effective photothermal agents (PTAs). Boron dipyrromethene (BODIPY) dyes, being well known for their high brightness and quantum efficiencies, are the antithesis of PTAs. Nonetheless, a systematic exploration of the photophysics and photothermal characteristics of a series of π-extended BODIPY dyes with high absorptivity in the near-infrared (NIR) region has achieved superior photothermal conversion efficiencies (>90%), in both monomeric state and nanoparticles after encapsulation in a biocompatible polyethyleneglycol 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000]. Optimal PTA candidates combine strong NIR absorption provided by extended donor-acceptor conjugation and an optimization of the electronic and steric effects of meso-substituents to maximize photothermal conversion performance. The PTT-optimized meso-CF3-BODIPY, TCF3PEn exhibits exceptional efficacy in inducing cancer cell apoptosis and in vivo tumor ablation using low-power NIR laser irradiation (0.3 W cm-2, 808 nm) as well as excellent biological safety, underscoring its potential for advancing light-induced cancer therapies.

Photothermal hydrogels for infection control and tissue regeneration.

In this review, we report investigating photothermal hydrogels, innovative biomedical materials designed for infection control and tissue regeneration. These hydrogels exhibit responsiveness to near-infrared (NIR) stimulation, altering their structure and properties, which is pivotal for medical applications. Photothermal hydrogels have emerged as a significant advancement in medical materials, harnessing photothermal agents (PTAs) to respond to NIR light. This responsiveness is crucial for controlling infections and promoting tissue healing. We discuss three construction methods for preparing photothermal hydrogels, emphasizing their design and synthesis, which incorporate PTAs to achieve the desired photothermal effects. The application of these hydrogels demonstrates enhanced infection control and tissue regeneration, supported by their unique photothermal properties. Although research progress in photothermal hydrogels is promising, challenges remain. We address these issues and explore future directions to enhance their therapeutic potential.

A thermoresponsive nanocomposite integrates NIR-II-absorbing small molecule with lonidamine for pyroptosis-promoted synergistic immunotherapy.

Photothermal immunotherapy is regarded as the ideal cancer therapeutic modality to against malignant solid tumors; however, its therapeutic benefits are often modest and require improvement. In this study, a thermoresponsive nanoparticle (BTN@LND) composed of a photothermal agent (PTA) and pyroptosis inducer (lonidamine) were developed to enhance immunotherapy applications. Specifically, our "two-step" donor engineering strategy produced the strong NIR-II-absorbing organic small-molecule PTA (BTN) that exhibited high NIR-II photothermal performance (ε1064 = 1.51 × 104 M-1 cm-1, η = 75.8%), and this facilitates the diagnosis and treatment of deep tumor tissue. Moreover, the fabricated thermally responsive lipid nanoplatform based on BTN efficiently delivered lonidamine to the tumor site and achieved spatiotemporal release triggered by the NIR-II photothermal effect. In vitro and in vivo experiments demonstrated that the NIR-II photothermal therapy (PTT)-mediated on-demand release of cargo effectively faciliated tumor cell pyroptosis, thereby intensifying the immunogenic cell death (ICD) process to promote antitumor immunotherapy. As a result, this intelligent component bearing photothermal and chemotherapy can maximally suppress the growth of tumors, thus providing a promising approach for pyroptosis/NIR-II PTT synergistic therapy against tumors.

Acceptor-donor-acceptor type organic photothermal agents with enhanced NIR absorption and photothermal conversion effect for cancer photothermal therapy.

Numerous photothermal agents (PTAs) require high-intensity and long-duration laser excitation for photothermal therapy (PTT), resulting in light damage to healthy skin and tissue as well as limiting their biomedical applications. Integrating desirable near-infrared (NIR) absorption and high photothermal conversion efficiency (PCE) into a single small-molecule PTA is an important prerequisite for realizing efficient PTT, but is a serious challenge. Herein, through molecular engineering strategy, an acceptor-donor-acceptor (A-D-A) type PTA (ADA3) was readily developed for 808 nm laser-driving photothermal imaging and PTT of tumor. Theoretical calculations and experiment results show molecular engineering strategy is significant in regulating the structure and energy gap of PTAs, so as to effectively induce a narrow band gap for NIR absorption and further optimize photothermal properties. ADA3 possesses molar extinction coefficient of 3.1 × 104 M-1 cm-1 at 808 nm, followed being assembled into nanoparticles, ADA3-NPs show high PCE of 80.3%. In vivo experiments indicate that ADA3-NPs have excellent antitumor capability under one-time, low-intensity and short-duration (808 nm, 330 mW/cm2, 3 min) laser irradiation. Therefore, this work definitely exemplifies the enormous potential of molecular engineering strategy and provides an effective method for developing small-molecule PTAs.

Recent Trends in Bio-nanomaterials and Non-invasive Combinatorial Approaches of Photothermal Therapy against Cancer.

In 2020, approximately 10 million deaths worldwide were attributed to cancer, making it the primary cause of death globally. Photothermal therapy (PTT) is one of the novel ways to treat and abolish cancer. PTT significantly impacts cancer theranostics compared to other therapies like surgery, chemotherapy, and radiotherapy due to its remarkable binding capability to tumor sites and lower invasiveness into normal healthy tissues. PTT relies on photothermal agents (PTAs), which generate heat by absorbing the near-infrared (NIR) light and destroying cancer cells. Several PTT agents remain longer in the reticuloendothelial system (RES) and induce toxicity, restricting their use in the biomedical field. To overcome this problem, the usage of biodegradable nano-photothermal agents is required. This review has discussed the PTT mechanism of action and different types of novel bio-nanomaterials used for PTT. We also focussed on the combinatorial effects of PTT with other cancer therapies and their effect on human health. The role of LED lights and mild hypothermia in PTT has been discussed briefly in this review.

Advances of Photothermal Agents with Fluorescence Imaging/Enhancement Ability in the Field of Photothermal Therapy and Diagnosis.

Photothermal therapy (PTT) is an effective cancer treatment method. Due to its easy focusing and tunability of the irradiation light, direct and accurate local treatment can be performed in a noninvasive manner by PTT. This treatment strategy requires the use of photothermal agents to convert light energy into heat energy, thereby achieving local heating and triggering biochemical processes to kill tumor cells. As a key factor in PTT, the photothermal conversion ability of photothermal agents directly determines the efficacy of PTT. In addition, photothermal agents generally have photothermal imaging (PTI) and photoacoustic imaging (PAI) functions, which can not only guide the optimization of irradiation conditions but also achieve the integration of disease diagnosis. If the photothermal agents have function of fluorescence imaging (FLI) or fluorescence enhancement, they can not only further improve the accuracy in disease diagnosis but also accurately determine the tumor location through multimodal imaging for corresponding treatment. In this paper, we summarize recent advances in photothermal agents with FLI or fluorescence enhancement functions for PTT and tumor diagnosis. According to the different recognition sites, the application of specific targeting photothermal agents is introduced. Finally, limitations and challenges of photothermal agents with fluorescence imaging/enhancement in the field of PTT and tumor diagnosis are prospected.

Research progress of organic photothermal agents delivery and synergistic therapy systems.

Cancer is currently one of the leading causes of mortality worldwide. Due to the inevitable shortcomings of conventional treatments, photothermal therapy (PTT) has attracted great attention as an emerging and non-invasive cancer treatment method. Photothermal agents (PTAs) is a necessary component of PTT to play its role. It accumulates at the tumor site through appropriate methods and converts the absorbed light energy into heat energy effectively under near-infrared light irradiation, thus increasing the temperature of the tumor area and facilitating ablation of the tumor cells. Compared to inorganic photothermal agents, which have limitations such as non-degradability and potential long-term toxicity in vivo, organic photothermal agents exhibit excellent biocompatibility and biodegradability, thus showing promising prospects for the application of PTT in cancer treatment. And these organic photothermal agents can also be engineered into nanoparticles to improve their water solubility, extend their circulation time in vivo, and specifically target tumors. Moreover, further combination of PTT with other treatment methods can effectively enhance the efficacy of cancer treatment and alleviate the side effects associated with single treatments. This article briefly introduces several common types of organic photothermal agents and their nanoparticles, and reviews the applications of PTT based on organic photothermal agents in combination with chemotherapy, photodynamic therapy, chemodynamic therapy, immunotherapy, and multimodal combination therapy for tumor treatment, which expands the ideas and methods in the field of tumor treatment.

Preparation and optimization of agarose or polyacrylamide/amino acid-based double network hydrogels for photocontrolled drug release.

The high water content and biocompatibility of amino-acid-based supramolecular hydrogels have generated growing interest in drug delivery research. Nevertheless, the existing dominant approach of constructing such hydrogels, the exploitation of a single amino acid type, typically comes with several drawbacks such as weak mechanical properties and long gelation times, hindering their applications. Here, we design a near-infrared (NIR) light-responsive double network (DN) structure, containing amino acids and different synthetic or natural polymers, i.e., polyacrylamide, poly(N-isopropylacrylamide), agarose, or low-gelling agarose. The hydrogels displayed high mechanical strength and high drug-loading capacity. Adjusting the ratio of Fmoc-Tyr-OH/Fmoc-Tyr(Bzl)-OH or Fmoc-Phe-OH/Fmoc-Tyr(Bzl)-OH, we could drastically shorten the gelation time of the DN hydrogels at room and body temperatures. Moreover, introducing photothermal agents (graphene oxide, carbon nanotubes, molybdenum disulfide nanosheets, or indocyanine green), we equipped the hydrogels with NIR responsivity. We demonstrated the light-triggered release of the drug baclofen, which is used in severe spasticity treatment. Rheology and stability tests confirmed the positive impact of the polymers on the mechanical strength of the hydrogels, while maintaining good stability under physiological conditions. Overall, our study contributed a novel hydrogel formulation with high mechanical resistance, rapid gel formation, and efficient NIR-controlled drug release, offering new opportunities for biomedical applications.

Configuration-mediated excited-state energy dissipation in metal-bridged dimeric D-A fluorophores for enhanced photothermal therapy.

Photothermal agents (PTAs) based on donor (D)-acceptor (A) NIR fluorophores show great promise in photothermal therapy due to their accessible molecular engineering to mediate excitation energy for high photothermal conversion. Except for molecular structural modification of D-A fluorophores, intermolecular arrangement in space greatly influences their excitation energy dissipation as well. But how to mediate their intermolecular arrangement is still challenging. Here we control the intermolecular orientation of chromophores via metal coordination to form Pt-bridged dimeric D-A fluorophores with different geometries. The formed configuration isomers show different intermolecular exciton coupling behaviors involving charge transfer (CT) evolution and internally limited molecular rotation, which greatly affect excited-energy dissipation. Compared with folded configuration with intense NIR emission (quantum yields (QYs) = 15.62 %), linear configuration favors non-radiative decays with low QYs (6.99 %) but enhanced photothermal conversion efficiency (PCE = 41.57 %). The self-assembled nanoparticles combining Pt-bridged dimeric D-A fluorophores with DSPE-PEG2000-RGD reveal superior photothermal therapeutic features with desirable biosafety. This research provides a new designing concept to mediate excited-state energy dissipation pathways at a sub-nano level for enhanced photothermal conversion. STATEMENT OF SIGNIFICANCE: D-A fluorophores as photothermal agents attract great attention in photothermal therapy due to their accessible molecular engineering. Besides molecular engineering of D-A fluorophores, the intermolecular packing manner is proven to greatly affect their excitation energy dissipation. But how to control intermolecular arrangement is still challenging. Here we control the intermolecular orientation of chromophores via metal coordination to form Pt-bridged dimeric D-A fluorophores with different geometries. Compared to the folded configuration, linear configuration facilitates charge transfer (CT) evolution and molecular rotation, which promotes non-radiative decays of excited energy for enhanced photothermal therapy.

Gold nanoparticle-mediated photothermal therapy guidance with multi-wavelength photomagnetic imaging.

Difficulty in heating tumors with high spatial selectivity while protecting surrounding healthy tissues from thermal harm is a challenge for cancer photothermal treatment (PTT). To mitigate this problem, PTT mediated by photothermal agents (PTAs) has been established as a potential therapeutic technique to boost selectivity and reduce damage to surrounding healthy tissues. Various gold nanoparticles (AuNP) have been effectively utilized as PTAs, mainly using strategies to target cancerous tissue and increase selective thermal damage. Meanwhile, imaging can be used in tandem to monitor the AuNP distribution and guide the PTT. Mainly, the parameters impacting the induced temperature can be determined using simulation tools before treatment for effective PTT. However, accurate simulations can only be performed if the amount of AuNPs accumulated in the tumor is known. This study introduces Photo-Magnetic Imaging (PMI), which can appropriately recover the AuNP concentration to guide the PTT. Using multi-wavelength measurements, PMI can provide AuNP concentration based on their distinct absorption spectra. Tissue-simulating phantom studies are conducted to demonstrate the potential of PMI in recovering AuNP concentration for PTT planning. The recovered AuNP concentration is used to model the temperature increase accurately in a small inclusion representing tumor using a multiphysics solver that takes into account the light propagation and heat diffusion in turbid media.

Targeted delivery of organic small-molecule photothermal materials with engineered extracellular vesicles for imaging-guided tumor photothermal therapy.

Imaging-guided photothermal therapy (PTT) for cancers recently gathered increasing focus thanks to its precise diagnosis and potent therapeutic effectiveness. Croconaine (CR) dyes demonstrate potential in expanding utility for near infrared (NIR) dyes in bio-imaging/theranostics. However, reports on CR dyes for PTT are scarce most likely due to the short of the efficacious delivery strategies to achieve specific accumulation in diseased tissues to induce PTT. Extracellular vesicles (EVs) are multifunctional nanoparticle systems that function as safe platform for disease theragnostics, which provide potential benefits in extensive biomedical applications. Here, we developed a novel delivery system for photothermal molecules based on a CR dye that exerts photothermal activity through CDH17 nanobody-engineered EVs. The formed CR@E8-EVs showed strong NIR absorption, excellent photothermal performance, good biological compatibility and superb active tumor-targeting capability. The CR@E8-EVs can not only visualize and feature the tumors through CR intrinsic property as a photoacoustic imaging (PAI) agent, but also effectively retard the tumor growth under laser irradiation to perform PTT. It is expected that the engineered EVs will become a novel delivery vehicle of small organic photothermal agents (SOPTAs) in future clinical PTT applications.

Elevating Second Near-Infrared Photothermal Conversion Efficiency of Hollow Gold Nanorod for a Precise Theranostic of Orthotopic Bladder Cancer.

The second near-infrared (NIR-II) window laser-activated agents have attracted broad interest in an orthotopic cancer theranostic. However, developing NIR-II photothermal agents (PTAs) with advanced photothermal conversion efficiency (PTCE) and tumor-specific response elevation remains a crucial challenge. Herein, a hollow gold nanorod (AuHNR) with a strong localized surface plasmon resonance (LSPR) peak in the NIR-II window was coated with MnO2 and chitosan to obtain AuHNR@MnO2@CS (termed AuMC) by a one-step method. Upon exposure to the tumor microenvironment (TME), the overexpressed GSH triggered degradation of the MnO2 layer to release Mn2+ and resulted in the PTCE elevation owing to exposure of the AuHNR. Consequently, photoacoustic and magnetic resonance imaging for accurate diagnosis, Mn2+-mediated chemodynamic therapy, and AuHNR elevating PT therapy for precise treatment could be achieved. Both in vitro and in vivo experiments confirmed the good performance of the AuMC on an orthotopic bladder cancer precise theranostic. This study provided NIR-II activated, TME-response PT conversion efficiency enhanced PTAs and offered a tumor-selective theranostic agent for orthotopic bladder cancer in clinical application.

A tumor microenvironment-activatable nanoplatform with phycocyanin-assisted in-situ nanoagent generation for synergistic treatment of colorectal cancer.

The in-situ generation of therapeutic agents in targeted lesions is promising for revolutionizing oncotherapy but is limited by the low production efficiency. Given the specific tumor microenvironment (TME) of colorectal cancer (CRC), i.e., mild acidity, overexpressed H2O2, glutathione (GSH) and H2S, we develop phycocyanin (PC) encapsulated PZTC/SS/HA nanocapsules (NCs) for TME-responsive, protein-assisted "turn-on'' therapy of CRC. The NCs are prepared by sequentially assembling Cu2+-tannic acid (TA) coordination shell, disulfide bond-bearing cross-linker, and hyaluronic acid (HA) on the sacrificial template ZIF-8, thus achieving pH-, GSH-responsiveness, and tumor targeting capability, respectively. Once reaching the CRC sites, the NCs can quickly disintegrate and release Cu2+ and PC, accompanied by subsequent endogenous H2S-triggered generation of copper sulfide (CuS). Significantly, the intracellular sulfidation process can be accelerated by PC, thereby enabling efficient photothermal therapy (PTT) under NIR-Ⅱ laser. Besides, Cu2+-associated chemodynamic therapy (CDT) can be simultaneously activated and enhanced by PTT-induced local hyperthermia and disulfide bond-induced GSH consumption. This CRC-targeted and TME-activated synergistic PTT/CDT strategy displays high therapeutic efficacy both in vitro and in vivo, which can open up a new avenue for biomolecule-assisted in-situ nanoagent generation and effective TME-responsive synergistic treatment of CRC.

Dual Behavior Regulation: Tether-Free Deep-Brain Stimulation by Photothermal and Upconversion Hybrid Nanoparticles.

Optogenetics has been plagued by invasive brain implants and thermal effects during photo-modulation. Here, two upconversion hybrid nanoparticles modified with photothermal agents, named PT-UCNP-B/G, which can modulate neuronal activities via photostimulation and thermo-stimulation under near-infrared laser irradiation at 980 nm and 808 nm, respectively, are demonstrated. PT-UCNP-B/G emits visible light (410-500 nm or 500-570 nm) through the upconversion process at 980 nm, while they exhibit efficient photothermal effect at 808 nm with no visible emission and tissue damage. Intriguingly, PT-UCNP-B significantly activates extracellular sodium currents in neuro2a cells expressing light-gated channelrhodopsin-2 (ChR2) ion channels under 980-nm irradiation, and inhibits potassium currents in human embryonic kidney 293 cells expressing the voltage-gated potassium channels (KCNQ1) under 808-nm irradiation in vitro. Furthermore, deep-brain bidirectional modulation of feeding behavior is achieved under tether-free 980 or 808-nm illumination (0.8 W cm-2 ) in mice stereotactically injected with PT-UCNP-B in the ChR2-expressing lateral hypothalamus region. Thus, PT-UCNP-B/G creates new possibility of utilizing both light and heat to modulate neural activities and provides a viable strategy to overcome the limits of optogenetics.

Manipulating Host-Guest Charge Transfer of a Water-Soluble Double-Cavity Cyclophane for NIR-II Photothermal Therapy.

Water-soluble small organic photothermal agents (PTAs) over NIR-II biowindow (1000-1350 nm) are highly desirable, but the rarity greatly limits their applications. Based on a water-soluble double-cavity cyclophane GBox-44+ , we report a class of host-guest charge transfer (CT) complexes as structurally uniform PTAs for NIR-II photothermal therapy. As a result of its high electron-deficiency, GBox-44+ can bind different electron-rich planar guests with a 1 : 2 host/guest stoichiometry to readily tune the CT absorption band that extends to the NIR-II region. When using a diaminofluorene guest substituted with an oligoethylene glycol chain, the host-guest system realized both good biocompatibility and enhanced photothermal conversion at 1064 nm, and was then exploited as a high-efficiency NIR-II PTA for cancer cell and bacterial ablation. This work broadens the potential applications of host-guest cyclophane systems and provides a new access to bio-friendly NIR-II photoabsorbers with well-defined structures.