Copper selenide nanosheets with photothermal therapy-related properties and multienzyme activity for highly effective eradication of drug resistance.

Bacterial infections are among the most significant causes of death in humans. Chronic misuse or uncontrolled use of antibiotics promotes the emergence of multidrug-resistant superbugs that threaten public health through the food chain and cause environmental pollution. Based on the above considerations, copper selenide nanosheets (CuSe NSs) with photothermal therapy (PTT)- and photodynamic therapy (PDT)-related properties have been fabricated. These CuSe NSs possess enhanced PDT-related properties and can convert O2 into highly toxic reactive oxygen species (ROS), which can cause significant oxidative stress and damage to bacteria. In addition, CuSe NSs can efficiently consume glutathione (GSH) at bacterial infection sites, thus further enhancing their sterilization efficacy. In vitro antibacterial experiments with near-infrared (NIR) irradiation have shown that CuSe NSs have excellent photothermal bactericidal properties. These experiments also showed that CuSe NSs exerted excellent bactericidal effects on wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) and significantly promoted the healing of infected wounds. Because of their superior biological safety, CuSe NSs are novel copper-based antimicrobial agents that are expected to enter clinical trials, serving as a modern approach to the major problem of treating bacterially infected wounds.

Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.

A novel multifunctional microneedle patch for synergistic photothermal- gas therapy against maxillofacial malignant melanoma and associated skin defects.

Considering the high recrudescence and the long-lasting unhealed large-sized wound that affect the aesthetics and cause dysfunction after resection of maxillofacial malignant skin tumors, a groundbreaking strategy is urgently needed. Photothermal therapy (PTT), which has become a complementary treatment of tumors, however, is powerless in tissue defect regeneration. Therefore, a novel multifunctional sodium nitroprusside and Fe2+ ions loaded microneedles (SNP-Fe@MNs) platform was fabricated by accomplishing desirable NIR-responsive photothermal effect while burst releasing nitric oxide (NO) after the ultraviolet radiation for the ablation of melanoma. Moreover, the steady releasing of NO in the long term by the platform can exert its angiogenic effects via upregulating multiple related pathways to promote tissue regeneration. Thus, the therapeutic dilemma caused by postoperative maxillofacial skin malignancies could be conquered through promoting tumor cell apoptosis via synergistic PTT-gas therapy and subsequent regeneration process in one step. The bio-application of SNP-Fe@MNs could be further popularized based on its ideal bioactivity and appealing features as a strategy for synergistic therapy of other tumors occurred in skin.

Melanin-Ce6-loaded polydopamine nanoparticles-based enhanced phototherapy for B16 melanoma cancer cells.

Melanoma is one of the most aggressive and lethal types of cancer owing to its metastatic propensity and chemoresistance property. An alternative therapeutic option is photodynamic and photothermal therapies (PDT/PTT), which employ near-infrared (NIR) light to generate heat and reactive oxygen species (ROS). As per previous reports, Melanin (Mel), and its synthetic analogs (i.e. polydopamine nanoparticles) can induce NIR light-mediated heat energy, thereby selectively targeting and ameliorating cancer cells. Similarly, chlorin e6 (Ce6) also has high ROS generation ability and antitumor activity against various types of cancer. Based on this tenet, In the current study, we have encapsulated Mel-Ce6 in a polydopamine (PDA) nanocarrier (MCP NPs) synthesized by the oxidation polymerization method. The hydrodynamic diameter of the synthesized spherical MCP NPs was 139 ± 10 nm. The MCP NPs, upon irradiation with NIR 690 nm laser for 6 min, showed photothermal efficacy of more than 50 °C. Moreover, the red fluorescence in the MCP NPs due to Ce6 can be leveraged for diagnostic purposes. Further, the MCP NPs exhibited considerable biocompatibility with the L929 cell line and exerted nearly 70% ROS-mediated cytotoxicity on the B16 melanoma cell line after the laser irradiation. Thus, the prepared MCP NPs could be a promising theranostic agent for treating the B16 melanoma cancer.

Tea polyphenol-derived nanomedicine for targeted photothermal thrombolysis and inflammation suppression.

Thrombotic diseases impose a significant global health burden, and conventional drug-based thrombolytic therapies are encumbered by the risk of bleeding complications. In this study, we introduce a novel drug-free nanomedicine founded on tea polyphenols nanoparticles (TPNs), which exhibits multifaceted capabilities for localized photothermal thrombolysis. TPNs were synthesized through a one-pot process under mild conditions, deriving from the monomeric epigallocatechin-3-gallate (EGCG). Within this process, indocyanine green (ICG) was effectively encapsulated, exploiting multiple intermolecular interactions between EGCG and ICG. While both TPNs and ICG inherently possessed photothermal potential, their synergy significantly enhanced photothermal conversion and stability. Furthermore, the nanomedicine was functionalized with cRGD for targeted delivery to activated platelets within thrombus sites, eliciting robust thrombolysis upon laser irradiation across diverse thrombus types. Importantly, the nanomedicine's potent free radical scavenging abilities concurrently mitigated vascular inflammation, thus diminishing the risk of disease recurrence. In summary, this highly biocompatible multifunctional nanomaterial holds promise as a comprehensive approach that combines thrombolysis with anti-inflammatory actions, offering precision in thrombosis treatment.

Analysis of Optimal Treatment Starting Time for Photothermal Therapy Through Analysis of Diffusion Behavior of Gold Nanoparticles.

Introduction: Due to its distinct advantage of non-invasive application in treatment, photothermal therapy (PTT) is being studied by many researchers to reduce the need for surgical incisions. It is characterized by the injection of nanoparticles into biological tissue as photothermal agents (PTAs) which diffuse within the tissue. In this study, the diffusion behavior of various doses of gold nanoparticles (AuNPs) injected into tumor tissues is analyzed and the effectiveness of PTT at each elapsed time after injection is confirmed by numerical analysis. Methods: The diffusion behavior of AuNPs within biological tissues is assessed using the convection-diffusion equation, while the temperature distribution is determined using the Pennes bioheat transfer equation. In addition, the effect of the diffusion behavior of AuNPs on the effectiveness of PTT is quantitatively confirmed by analyzing the temperature distribution in the medium through the apoptotic variable. Numerical simulation parameters are selected with doses ranging from 100 to 400 µg/mL, elapsed time after injection from 1 min to 24 h, and laser power ranging from 0 to 1 W. Results: After evaluating PTT's efficacy in every situation, it was discovered that a dosage of 100-300 µg/mL produced the best therapeutic result, with the highest impact occurring 12 hours after injection. In contrast, when the dosage was 400 µg/mL, the highest therapeutic effect was achieved after 18 hours post-injection. Additionally, it was discovered that the ideal laser power at each injection dose was 0.22, 0.14, 0.12, and 0.12 W, respectively. Conclusion: The conditions required to achieve the optimal treatment effect at each dosage, presented here, are expected to accelerate the commercialization of PTT.

Multimodal phototherapy agents target lipid droplets for near-infrared imaging-guided type I photodynamic/photothermal therapy.

The construction and optimization of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy (PDT), and photothermal therapy (PTT) functions remain challenging. In this study, we aimed to design and synthesize four donor-acceptor (D-A) type aggregation-induced emission molecules: PSI, TPSI, PSSI, and TPSSI. We employed phenothiazine as an electron donor and 1,3-bis(dicyanomethylidene)indan as a strong electron acceptor in the synthesis process. Among them, TPSSI exhibited efficient type I reactive oxygen species generation, high photothermal conversion efficiency (45.44 %), and near-infrared emission. These observations can be attributed to the introduction of a triphenylamine electron donor group and a thiophene unit, which resulted in increased D-A strengths, a reduced singlet-triplet energy gap, and increased free intramolecular motion. TPSSI was loaded into bovine serum albumin to prepare biocompatible TPSSI nanoparticles (NPs). Our results have indicated that TPSSI NPs can target lipid droplets with negligible dark toxicity and can efficiently generate O2•- in hypoxic tumor environments. Moreover, TPSSI NPs selectively targeted 4T1 tumor tissues and exhibited a good PDT-PTT synergistic effect in vitro and in vivo. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technologies. STATEMENT OF SIGNIFICANCE: The construction of a single phototherapeutic agent with photoluminescence, type I photodynamic therapy, and photothermal therapy functions, and its optimization remain challenging. In this study, we construct four donor-acceptor aggregation-induced emission molecules using phenothiazine as an electron donor and 1,3-Bis(dicyanomethylidene)indan as a strong electron acceptor. By optimizing the molecular structure, an integrated phototherapy agent with fluorescence imaging ability and high photodynamic / photothermal therapy performance was prepared. We believe that the successful preparation of multifunctional phototherapeutic agents will promote the development of efficient tumor diagnosis and treatment technology.

J-Aggregate Promoting NIR-II Emission for Fluorescence/Photoacoustic Imaging-Guided Phototherapy.

J-aggregate is a promising strategy to enhance second near-infrared window (NIR-II) emission, while the controlled synthesis of J-aggregated NIR-II dyes is a huge challenge because of the lack of molecular design principle. Herein, bulk spiro[fluorene-9,9'-xanthene] functionalized benzobisthiadiazole-based NIR-II dyes (named BSFX-BBT and OSFX-BBT) are synthesized with different alkyl chains. The weak repulsion interaction between the donor and acceptor units and the S…N secondary interactions make the dyes to adopt a co-planar molecular conformation and display a peak absorption >880 nm in solution. Importantly, BSFX-BBT can form a desiring J-aggregate in the condensed state, and femtosecond transient absorption spectra reveal that the excited states of J-aggregate are the radiative states, and J-aggregate can facilitate stimulated emission. Consequently, the J-aggregated nanoparticles (NPs) display a peak emission at 1124 nm with a high relative quantum yield of 0.81%. The efficient NIR-II emission, good photothermal effect, and biocompatibility make the J-aggregated NPs demonstrate efficient antitumor efficacy via fluorescence/photoacoustic imaging-guided phototherapy. The paradigm illustrates that tuning the aggregate states of NIR-II dye via spiro-functionalized strategy is an effective approach to enhance photo-theranostic performance.

Bithiophene-Functionalized Infrared Two-Photon Absorption Metal Complexes as Single-Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy.

A planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single-molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two-photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA-related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin-resistant non-small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two-photon activatable metal complex may contribute to a new generation of single-molecule-based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

Red blood cell membrane-camouflaged gold-core silica shell nanorods for cancer drug delivery and photothermal therapy.

Gold core mesoporous silica shell (AuMSS) nanorods are multifunctional nanomedicines that can act simultaneously as photothermal, drug delivery, and bioimaging agents. Nevertheless, it is reported that once administrated, nanoparticles can be coated with blood proteins, forming a protein corona, that directly impacts on nanomedicines' circulation time, biodistribution, and therapeutic performance. Therefore, it become crucial to develop novel alternatives to improve nanoparticles' half-life in the bloodstream. In this work, Polyethylenimine (PEI) and Red blood cells (RBC)-derived membranes were combined for the first time to functionalize AuMSS nanorods and simultaneously load acridine orange (AO). The obtained results revealed that the RBC-derived membranes promoted the neutralization of the AuMSS' surface charge and consequently improved the colloidal stability and biocompatibility of the nanocarriers. Indeed, the in vitro data revealed that PEI/RBC-derived membranes' functionalization also improved the nanoparticles' cellular internalization and was capable of mitigating the hemolytic effects of AuMSS and AuMSS/PEI nanorods. In turn, the combinatorial chemo-photothermal therapy mediated by AuMSS/PEI/RBC_AO nanorods was able to completely eliminate HeLa cells, contrasting with the less efficient standalone therapies. Such data reinforce the potential of AuMSS nanomaterials to act simultaneously as photothermal and chemotherapeutic agents.

Laser-Synthesized Germanium Nanoparticles as Biodegradable Material for Near-Infrared Photoacoustic Imaging and Cancer Phototherapy.

Biodegradable nanomaterials can significantly improve the safety profile of nanomedicine. Germanium nanoparticles (Ge NPs) with a safe biodegradation pathway are developed as efficient photothermal converters for biomedical applications. Ge NPs synthesized by femtosecond-laser ablation in liquids rapidly dissolve in physiological-like environment through the oxidation mechanism. The biodegradation of Ge nanoparticles is preserved in tumor cells in vitro and in normal tissues in mice with a half-life as short as 3.5 days. Biocompatibility of Ge NPs is confirmed in vivo by hematological, biochemical, and histological analyses. Strong optical absorption of Ge in the near-infrared spectral range enables photothermal treatment of engrafted tumors in vivo, following intravenous injection of Ge NPs. The photothermal therapy results in a 3.9-fold reduction of the EMT6/P adenocarcinoma tumor growth with significant prolongation of the mice survival. Excellent mass-extinction of Ge NPs (7.9 L g-1 cm-1 at 808 nm) enables photoacoustic imaging of bones and tumors, following intravenous and intratumoral administrations of the nanomaterial. As such, strongly absorbing near-infrared-light biodegradable Ge nanomaterial holds promise for advanced theranostics.

Ultrathin Cu9S5 Nanosheets with Sulfur Vacancy for Multimodal Tumor Therapy.

Multimodal tumor therapy with nanotechnology is an effective and integrative strategy to overcome the limitations of therapeutic efficacy and possible side effects associated with monotherapy. However, the construction of multimodal treatment nanoplatforms often involves various functional components, leading to certain challenges, such as time-consuming synthesis processes, low product yield, and inadequate biocompatibility. To address these issues, we have developed a straightforward method for preparing ultrathin Cu9S5 nanosheets (NSs) with surface defects for photothermal/photodynamic/chemodynamic therapy. The ultrathin morphology of the Cu9S5 NSs (with 2-3 nm) not only confers excellent biocompatibility but also enables broad-spectrum absorption with a remarkable photothermal conversion efficiency (58.96%) under 1064 nm laser irradiation. Moreover, due to the presence of a S vacancy, these Cu9S5 NSs exhibit favorable enzyme-like properties, including reactive oxygen species generation and glutathione consumption, particularly under laser irradiation. The efficacy of related tumor therapy and antibacterial treatment is significantly enhanced by the synergistic activation of photothermal/photodynamic/chemodynamic therapy through 1064 nm laser irradiation, as demonstrated by both in vitro and in vivo experiments. This study presents a novel strategy for multimodal tumor therapy with the prepared ultrathin Cu9S5 NSs, which holds promising pathways for photodynamic therapy in the NIR-II region.

Ti2C3 MXene-based nanocomposite as an intelligent nanoplatform for efficient mild hyperthermia treatment.

Photothermal therapy (PTT) has attracted much attention due to its less invasive, controllable and highly effective nature. However, PTT also suffers from intrinsic cancer resistance mediated by cell survival pathways. These survival pathways are regulated by a variety of proteins, among which heat shock protein (HSP) triggers thermotolerance and protects tumor cells from hyperthermia-induced apoptosis. Confronted by this challenge, we propose and validate here a novel MXene-based HSP-inhibited mild photothermal platform, which significantly enhances the sensitivity of tumor cells to heat-induced stress and thus improves the PPT efficacy. The Ti3C2@Qu nanocomposites are constructed by utilizing the high photothermal conversion ability of Ti3C2 nanosheets in combination with quercetin (Qu) as an inhibitor of HSP70. Qu molecules are loaded onto the nanoplatform in a pH-sensitive controlled release manner. The acidic environment of the tumor causes the burst-release of Qu molecules, which deplete the level of heat shock protein 70 (HSP70) in tumor cells and leave the tumor cells out from the protection of the heat-resistant survival pathway in advance, thus sensitizing the hyperthermia efficacy. The nanostructure, photothermal properties, pH-responsive controlled release, synergistic photothermal ablation of tumor cells in vitro and in vivo, and hyperthermia effect on subcellular structures of the Ti3C2@Qu nanocomposites were systematically investigated.

Multifunctional Inorganic-Organic Composite Carriers for Synergistic Dual Therapy of Melanoma.

Many methods for cancer treatment have been developed. Among them photothermal therapy (PTT) has drawn the most significant attention due to its noninvasiveness, remote control activation, and low side effects. However, a limited depth of light penetration of PTT is the main drawback. To improve the therapeutic efficiency, the development of combined PTT with other therapeutic agents is highly desirable. In this work, we have designed multifunctional composite carriers based on polylactic acid (PLA) particles decorated with gold nanorods (Au NRs) as nanoheaters and selenium nanoparticles (Se NPs) for reactive oxygen species (ROS) production in order to perform a combined PTT against B16-F10 melanoma. To do this, we have optimized the synthesis of PLA particles modified with Se NPs and Au NRs (PLA-Se:Au), studied the cellular interactions of PLA particles with B16-F10 cells, and analyzed in vivo biodistribution and tumor inhibition efficiency. The results of in vitro and in vivo experiments demonstrated the synergistic effect from ROS induced by Se NPs and the heating from Au NRs. In melanoma tumor-bearing mice, intratumoral injection of PLA-Se:Au followed by laser irradiation leads to almost complete elimination of tumor tissues. Thus, the optimal photothermal properties and ROS-generating capacity allow us to recommend PLA-Se:Au as a promising candidate for the development of the combined PTT against melanoma.

Oxidized cellulose-filled double thermo/pH-sensitive hydrogel for local chemo-photothermal therapy in breast cancer.

Lumpectomy plus radiation is a treatment option offering better survival than conventional mastectomy for patients with early-stage breast cancer. However, successive radioactive therapy remains tedious and unsafe with severe adverse reactions and secondary injury. Herein, a composite hydrogel with pH- and photothermal double-sensitive activity is developed via physical crosslinking. The composite hydrogel incorporated with tempo-oxidized cellulose nanofiber (TOCN), polyvinyl alcohol (PVA) and a polydopamine (PDA) coating for photothermal therapy (PTT) triggered in situ release of doxorubicin (DOX) drug was utilized to optimize postoperative strategies of malignant tumors inhibition. The incorporation of TOCN significantly affects the performance of composite hydrogels. The best-performing TOCN/PVA7 was selected for drug loading and polydopamine coating by rational design. In vitro studies have demonstrated that the composite hydrogel exhibited high NIR photothermal conversion efficiency, benign cytotoxicity to L929 cells, pH-dependent release profiles, and strong MCF-7 cell inhibitory effects. Then the TOCN/PVA7-PDA@DOX hydrogel is implanted into the tumor resection cavity for local in vivo chemo-photothermal synergistical therapy to ablate residue tumor tissues. Overall, this work suggests that such a chemo-photothermal hydrogel delivery system has great potential as a promising tool for the postsurgical management of breast cancer.

MRI-guided cell membrane-camouflaged bimetallic coordination nanoplatform for combined tumor phototherapy.

Nanotechnology for tumor diagnosis and optical therapy has attracted widespread interest due to its low toxicity and convenience but is severely limited due to uncontrollable tumor targeting. In this work, homologous cancer cell membrane-camouflaged multifunctional hybrid metal coordination nanoparticles (DRu/Gd@CM) were prepared for MRI-guided photodynamic therapy (PDT) and photothermal therapy (PTT) of tumors. Bimetallic coordination nanoparticles are composed of three functional modules: dopamine, Ru(dcbpy)3Cl2 and GdCl3, which are connected through 1,4-Bis[(1H-imidazole-1-yl)methyl]benzene (BIX). Their morphology can be easily controlled by adjusting the ratio of precursors. Optimistically, the intrinsic properties of the precursors, including the photothermal properties of polydopamine (PDA), the magnetic resonance (MR) response of Gd3+, and the singlet oxygen generation of Ru(dcbpy)3Cl2, are well preserved in the hybrid metal nanoparticles. Furthermore, the targeting of homologous cancer cell membranes enables these coordinated nanoparticles to precisely target tumor cells. The MR imaging capabilities and the combination of PDT and PTT were demonstrated in in vitro experiments. In addition, in vivo experiments indicated that the nanoplatform showed excellent tumor accumulation and therapeutic effects on mice with subcutaneous tumors, and could effectively eliminate tumors within 14 days. Therefore, it expanded the new horizon for the preparation of modular nanoplatform and imaging-guided optical therapy of tumors.

Suitable Isolation Side Chains: A Simple Strategy for Simultaneously Improving the Phototherapy Efficacy and Biodegradation Capacities of Conjugated Polymer Nanoparticles.

Utilizing one molecule to realize combinational photodynamic and photothermal therapy upon single-wavelength laser excitation, which relies on a multifunctional phototherapy agent, is one of the most cutting-edge research directions in tumor therapy owing to the high efficacy achieved over a short course of treatment. Herein, a simple strategy of "suitable isolation side chains" is proposed to collectively improve the fluorescence intensity, reactive oxygen species production, photothermal conversion efficiency, and biodegradation capacity. Both in vitro and in vivo results reveal the practical value and huge potential of the designed biodegradable conjugated polymer PTD-C16 with suitable isolation side chains in fluorescence image-guided combinational photodynamic and photothermal therapy. These improvements are achieved through manipulation of aggregated states by only side chain modification without changing any conjugated structure, providing new insight into the design of biodegradable high-performance phototherapy agents.

Enhancing Photothermal/Photodynamic Therapy for Glioblastoma by Tumor Hypoxia Alleviation and Heat Shock Protein Inhibition Using IR820-Conjugated Reduced Graphene Oxide Quantum Dots.

We use low-molecular-weight branched polyethylenimine (PEI) to produce cytocompatible reduced graphene oxide quantum dots (rGOQD) as a photothermal agent and covalently bind it with the photosensitizer IR-820. The rGOQD/IR820 shows high photothermal conversion efficiency and produces reactive oxygen species (ROS) after irradiation with near-infrared (NIR) light for photothermal/photodynamic therapy (PTT/PDT). To improve suspension stability, rGOQD/IR820 was PEGylated by anchoring with the DSPE hydrophobic tails in DSPE-PEG-Mal, leaving the maleimide (Mal) end group for covalent binding with manganese dioxide/bovine serum albumin (MnO2/BSA) and targeting ligand cell-penetrating peptide (CPP) to synthesize rGOQD/IR820/MnO2/CPP. As MnO2 can react with intracellular hydrogen peroxide to produce oxygen for alleviating the hypoxia condition in the acidic tumor microenvironment, the efficacy of PDT could be enhanced by generating more cytotoxic ROS with NIR light. Furthermore, quercetin (Q) was loaded to rGOQD through π-π interaction, which can be released in the endosomes and act as an inhibitor of heat shock protein 70 (HSP70). This sensitizes tumor cells to thermal stress and increases the efficacy of mild-temperature PTT with NIR irradiation. By simultaneously incorporating the HSP70 inhibitor (Q) and the in situ hypoxia alleviating agent (MnO2), the rGOQD/IR820/MnO2/Q/CPP can overcome the limitation of PTT/PDT and enhance the efficacy of targeted phototherapy in vitro. From in vivo study with an orthotopic brain tumor model, rGOQD/IR820/MnO2/Q/CPP administered through tail vein injection can cross the blood-brain barrier and accumulate in the intracranial tumor, after which NIR laser light irradiation can shrink the tumor and prolong the survival times of animals by simultaneously enhancing the efficacy of PTT/PDT to treat glioblastoma.

Multifunctional agents based on 3-dicycanovinylindan-1-one acceptor: Molecular design and phototheranostic application.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), has garnered considerable attention in recent years, owing to its precise spatiotemporal accuracy with minimal side effects. Recent research reveals that the combination of PDT and PTT exhibits a remarkable anti-tumor efficacy compared to PDT or PTT alone, which has put forward the new requirements of multifunctional phototherapy agents with both high photosensitization and photothermal conversion efficiencies. Among the newly developed multifunctional agents, the ones with one or two 3-dicycanovinylindan-1-one (IC) moieties as the acceptors attract much more attention, due to their long-wavelength excitation and emission, as well as high phototherapy efficacies. Therefore, in this review, the latest advancement of multifunctional agents based on IC acceptor is summarized. Especially, we focus on the structure-property relationships of the agents, as well as their biomedical application in anti-tumor therapy or image-guided therapy. Our perspective on the further future development of this field is also discussed to conclude.

Rotor-based image-guided therapy of glioblastoma.

Glioblastoma (GBM), deep in the brain, is more challenging to diagnose and treat than other tumors. Such challenges have blocked the development of high-impact therapeutic approaches that combine reliable diagnosis with targeted therapy. Herein, effective cyanine dyes (IRLy) with the near-infrared two region (NIR-II) adsorption and aggregation-induced emission (AIE) have been developed via an "extended conjugation & molecular rotor" strategy for multimodal imaging and phototherapy of deep orthotopic GBM. IRLy was synthesized successfully through a rational molecular rotor modification with stronger penetration, higher signal-to-noise ratio, and a high photothermal conversion efficiency (PCE) up to ∼60%, which can achieve efficient NIR-II photo-response. The multifunctional nanoparticles (Tf-IRLy NPs) were further fabricated to cross the blood-brain barrier (BBB) introducing transferrin (Tf) as a targeting ligand. Tf-IRLy NPs showed high biosafety and good tumor enrichment for GBM in vitro and in vivo, and thus enabled accurate, efficient, and less invasive NIR-II multimodal imaging and photothermal therapy. This versatile Tf-IRLy nanosystem can provide a reference for the efficient, precise and low-invasive multi-synergistic brain targeted photo-theranostics. In addition, the "extended conjugation & molecular rotor" strategy can be used to guide the design of other photothermal agents.