Three Strategies in Engineering Nanomedicines for Tumor Microenvironment-Enabled Phototherapy.

Canonical phototherapeutics have several limitations, including a lack of tumor selectivity, nondiscriminatory phototoxicity, and tumor hypoxia aggravation. The tumor microenvironment (TME) is characterized by hypoxia, acidic pH, and high levels of H2 O2 , GSH, and proteases. To overcome the shortcomings of canonical phototherapy and achieve optimal theranostic effects with minimal side effects, unique TME characteristics are employed in the development of phototherapeutic nanomedicines. In this review, the effectiveness of three strategies for developing advanced phototherapeutics based on various TME characteristics is examined. The first strategy involves targeted delivery of phototherapeutics to tumors with the assistance of TME-induced nanoparticle disassembly or surface modification. The second strategy involves near-infrared absorption increase-induced phototherapy activation triggered by TME factors. The third strategy involves enhancing therapeutic efficacy by ameliorating TME. The functionalities, working principles, and significance of the three strategies for various applications are highlighted. Finally, possible challenges and future perspectives for further development are discussed.

Hemoglobin Nanocrystals for Drugs Free, Synergistic Theranostics of Colon Tumor.

The conventional approach in cancer nanomedicine involves advanced drug nanocarriers delivering preloaded therapeutics to targeted tumor sites to maximize drug efficiency. However, both cancer drugs and nanocarriers inevitably produce side effects and systemic toxicity. Herein, hemoglobin nanocrystals (HbC) as drug-free theranostic nanoformulations with the tumor microenvironment (TME) activated diagnostic and therapeutic abilities towards colon tumors are introduced. HbC can release Fe2+ oxidized to Fe3+ in the Fenton reaction with tumor endogenous H2 O2 , concurrently with the generation of cytotoxic hydroxyl radicals (•OH) that allow for chemodynamic therapy (CDT). Furthermore, in situ-produced Fe3+ reacts with colon tumor-abundant H2 S, resulting in the production of Fe1- x S, which provides magnetic resonance imaging (MRI) contrast and allows for NIR light-inducible photothermal therapy (PTT). In vitro and in vivo studies revealed that HbC produced CDT towards 4T1 tumors, and MRI-guided, synergistically enhanced combination of CDT and PTT against H2 S abundant colon tumors (CT26), with negligible toxicity towards normal tissues, enlightening HbC as highly efficient and biocompatible TME activated theranostic nanoplatform specific against colon cancer without any traditional drugs and drug carriers.

Collaborative Design of MgO/FeOx Nanosheets on Titanium: Combining Therapy with Regeneration.

The repair of bone defects caused by osteosarcoma resection remains a clinical challenge because of the tumor recurrence and bacterial infection. Combining tumor and bacterial therapy with bone regeneration properties in bone implants is a promising strategy for the treatment of osteosarcoma. Here, a layer of MgO/FeOx nanosheet is constructed on the Ti implant to prevent tumor recurrence and bacterial infection, while simultaneously accelerating bone formation. This MgO/FeOx double metal oxide demonstrates good peroxidase activity to catalyze H2 O2 , which is rich in tumor microenvironment, to form reactive oxygen species (ROS), and shows good photothermal conversion capacity to produce photothermal effect, thus synergistically killing tumor cells and eliminating tumor tissue. In addition, it generates a local alkaline surface microenvironment to inhibit the energy metabolism of bacteria to enhance the photothermal antibacterial effect. Furthermore, benefiting from the generation of a Mg ion-containing alkaline microenvironment, this MgO/FeOx film can promote the osteogenic differentiation of osteoblast and angiogenesis of vascular endothelial cells in vitro as well as accelerated bone formation in vivo. This study proposes a multifunctional platform for integrating tumor and bacterial therapy and bone regeneration, which has good application prospects for the treatment of osteosarcoma.

NIR-II Perylene Monoimide-Based Photothermal Agent with Strengthened Donor-Acceptor Conjugation for Deep Orthotopic Glioblastoma Phototheranostics.

Extensive efforts have been devoted to the design of organic photothermal agents (PTAs) that absorb in the second near-infrared (NIR-II) bio-window, which can provide deeper tissue penetration that is significant for phototheranostics of lethal brain tumors. Herein, the first example of NIR-II-absorbing small organic molecule (N1) derived from perylene monoamide (PMI) and its bio-application after nano-encapsulation of N1 to function as a nano-agent for phototheranostics of deep orthotopic glioblastoma (GBM) is reported. By adopting a dual modification strategy of introducing a donor-acceptor unit and extending π-conjugation, the obtained N1 can absorb in 1000-1400 nm region and exhibit high photothermal conversation due to the apparent intramolecular charge transfer (ICT). A choline analogue, 2-methacryloyloxyethyl phosphorylcholine, capable of interacting specifically with receptors on the surface of the blood-brain barrier (BBB), is used to fabricate the amphiphilic copolymer for the nano-encapsulation of N1. The obtained nanoparticles demonstrate efficient BBB-crossing due to the receptor-mediated transcytosis as well as the small nanoparticle size of approximately 26 nm. The prepared nanoparticles exhibit excellent photoacoustic imaging and significant growth inhibition of deep orthotopic GBM. The current study demonstrates the enormous potential of PMI-based NIR-II PTAs and provides an efficient phototheranostic paradigm for deep orthotopic GBM.

Carrier-Free H2 O2 Self-Supplier for Amplified Synergistic Tumor Therapy.

Chemodynamic therapy (CDT) utilizes Fenton or Fenton-like reactions to convert hydrogen peroxide (H2 O2 ) into cytotoxic hydroxyl radicals (•OH) and draws extensive interest in tumor therapy. Nevertheless, high concentrations of glutathione (GSH) and insufficient endogenous H2 O2 often cause unsatisfactory therapeutic efficacy. Herein, a GSH-depleting and H2 O2 self-providing carrier-free nanomedicine that can efficiently load indocyanine green (ICG), ß-lapachone (LAP), and copper ion (Cu2+ ) (ICG-Cu2+ -LAP, LICN) to mediate synergetic photothermal and chemotherapy in enhanced chemodynamic therapy is designed. The results show that  LICNs successfully enter tumors owing to the enhanced permeability and retention effect. Through the reductive intracellular environment, Cu2+ in LICN can react with intracellular GSH, alleviate the antioxidant capacity of tumor tissues, and trigger the release of drugs. When LICN is subjected to near-infrared (NIR) irradiation, enhanced photothermal effect and upregulated expression of NAD(P)H quinone oxidoreductase-1 (NQO1) are observed. Meanwhile, the released LAP not only supports chemotherapy but also catalyzes NQO1 and produces sufficient endogenous H2 O2 , thereby increasing the efficiency of Cu+ -based Fenton-like reaction. Notably, GSH depletion and H2 O2 self-sufficiency generate sufficient •OH and kill tumor cells with high specificity. Overall, the study provides an innovative strategy to self-regulate GSH and H2 O2 levels for effective anticancer therapy.

Antigen Capture and Immune Modulation by Bacterial Outer Membrane Vesicles as In Situ Vaccine for Cancer Immunotherapy Post-Photothermal Therapy.

Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT). 1-MT@OMV-Mal can bind to the released tumor antigens after PTT, and be efficiently recognized and taken up by dendritic cells. Furthermore, in situ injection of 1-MT@OMV-Mal simultaneously overcomes the immune inhibition of IDO on tumor-infiltrating effector T cells, leading to remarkable inhibition on both primary and distant tumors. Together, a promising in situ vaccine based on OMVs to facilitate immune-mediated tumor clearance after PTT through orchestrating antigen capture and immune modulation is presented.

Starch Capped Atomically Thin CuS Nanocrystals for Efficient Photothermal Therapy.

Photothermal therapy requires efficient plasmonic nanomaterials with small size, good water dispersibility, and biocompatibility. This work reports a one-pot, 2-min synthesis strategy for ultrathin CuS nanocrystals (NCs) with precisely tunable size and localized surface plasmon resonance (LSPR), where a single-starch-layer coating leads to a high LSPR absorption at the near-IR wavelength 980 nm. The CuS NC diameter increases from 4.7 (1 nm height along [101]) to 28.6 nm (4.9 nm height along [001]) accompanied by LSPR redshift from 978 to 1200 nm, as the precursor ratio decreases from 1 to 0.125. Photothermal temperature increases by 38.6 °C in 50 mg L-1 CuS NC solution under laser illumination (980 nm, 1.44 W cm-2 ). Notably, 98.4% of human prostate cancer PC-3/Luc+ cells are killed by as little as 5 mg L-1 starch-coated CuS NCs with 3-min laser treatment, whereas CuS NCs without starch cause insignificant cell death. LSPR modeling discloses that the starch layer enhances the photothermal effect by significantly increasing the free carrier density and blue-shifting the LSPR toward 980 nm. This study not only presents a new type of photothermally highly efficient ultrathin CuS NCs, but also offers in-depth LSPR modeling investigations useful for other photothermal nanomaterial designs.

Dynamically PEGylated and Borate-Coordination-Polymer-Coated Polydopamine Nanoparticles for Synergetic Tumor-Targeted, Chemo-Photothermal Combination Therapy.

Multifunctional nanomaterials with efficient tumor-targeting and high antitumor activity are highly anticipated in the field of cancer therapy. In this work, a synergetic tumor-targeted, chemo-photothermal combined therapeutic nanoplatform based on a dynamically PEGylated, borate-coordination-polymer-coated polydopamine nanoparticle (PDA@CP-PEG) is developed. PEGylation on the multifunctional nanoparticles is dynamically achieved via the reversible covalent interaction between the surface phenylboronic acid (PBA) group and a catechol-containing poly(ethylene glycol) (PEG) molecule. Due to the acid-labile PBA/catechol complex and the weak-acid-stable PBA/sialic acid (SA) complex, the nanoparticles can exhibit a synergetic targeting property for the SA-overexpressed tumor cells, i.e., the PEG-caused "passive targeting" and PBA-triggered "active targeting" under the weakly acidic tumor microenvironment. In addition, the photothermal effect of the polydopamine core and the doxorubicin-loading capacity of the porous coordination polymer layer endow the nanoparticles with the potential for chemo-photothermal combination therapy. As expected, the in vitro and in vivo studies both verify that the multifunctional nanoparticles possess relatively lower systematic toxicity, efficient tumor targeting ability, and excellent chemo-photothermal activity for tumor inhibition. It is believed that these multifunctional nanoparticles with synergetic tumor targeting property and combined therapeutic strategies would provide an insight into the design of a high-efficiency antitumor nanoplatform for potential clinical applications.

Engineering Gold Nanorod-Copper Sulfide Heterostructures with Enhanced Photothermal Conversion Efficiency and Photostability.

Plasmonic gold nanorods (Au NRs)-copper sulfide heterostructures have recently attracted much attention owing to the synergistically enhanced photothermal properties. However, the facile synthesis and interface tailoring of Au NRs-copper sulfide heterostructures remain a formidable challenge. In this study, the rational design and synthesis of Au NRs-Cu7 S4 heterostructures via a one-pot hydrothermal process is reported. Specifically, core-shell and dumbbell-like Au NRs-Cu7 S4 heterostructures are obtained with well-controlled interfaces by employing the Au NRs with different aspect ratios. Both core-shell and dumbbell-like Au NRs-Cu7 S4 have proven effective as photothermal therapy agents, which offer both high photothermal stability and significant photothermal conversion efficiency up to 62%. The finite-difference time domain simulation results confirm the coupling effect that leads to the enhanced local field as well as the optical absorption at the heterostructure interface. Importantly, these Au NRs-Cu7 S4 heterostructures can be compatibly used as an 808 nm laser-driven photothermal therapy agents for the efficient photothermal therapy of cancer cells in vitro. This study will provide new insight into the design of other noble metal-semiconductor heterostructures for a broad range of applications utilizing surface plasmon resonance enhancement phenomena.

[Targeted Bifunctional Proteins and Hybrid Nanoconstructs for Cancer Diagnostics and Therapies].

In this review, the authors' works published within the past 5 years devoted to the development of bifunctional hybrid nanostructures based on the targeting polypeptides and nanoparticles of various origin (quantum dots, nanogold, nanodiamonds, upconversion nanoparticles, magnetic and polymer nanoparticles) as modules that ensure visualization and various damaging effects on cancer cells are surveyed and the prospects of their application in theranostics and precision medicine have been contemplated.

Multifunctional Mesoporous Silica Nanoparticles with Thermal-Responsive Gatekeeper for NIR Light-Triggered Chemo/Photothermal-Therapy.

In this work, a matrix metalloproteinase (MMP)-triggered tumor targeted mesoporous silica nanoparticle (MSN) is designed to realize near-infrared (NIR) photothermal-responsive drug release and combined chemo/photothermal tumor therapy. Indocyanine green (ICG) and doxorubicin (DOX) are both loaded in the MSN modified with thermal-cleavable gatekeeper (Azo-CD), which can be decapped by ICG-generated hyperthermia under NIR illumination. A peptidic sequence containing a short PEG chain, matrix metalloproteinase (MMP) substrate (PLGVR) and tumor cell targeting motif (RGD) are further decorated on the MSN via a host-guest interaction. The PEG chain can protect the MSN during the circulation and be cleaved off in the tumor tissues with overexpressed MMP, and then the RGD motif is switched on to target tumor cells. After the tumor-triggered targeting process, the NIR irradiation guided by ICG fluorescence can trigger cytosol drug release and realize combined chemo/photothermal therapy.

Inflammation-Targeting Mesenchymal Stem Cells Combined with Photothermal Treatment Attenuate Severe Joint Inflammation.

Current clinical therapeutic efficacy for the treatment of osteo- and rheumatoid-arthritis is obviously limited. Although mesenchymal stem cells (MSCs) are considered as a source of promising regenerative therapy, un-modified or genetically engineered MSCs injected in vivo restrict their clinical utility because of the low drug efficacy and unpredicted side effect, respectively. Herein, a strategy to enhance the migration efficacy of MSCs to inflamed joints via an inflammation-mediated education process is demonstrated. To reinforce the limited anti-inflammatory activity of MSCs, gold nanostar loaded with triamcinolone is conjugated to MSC. Furthermore, near-infrared laser-assisted photothermal therapy (PTT) induced by gold nanostar significantly elevates the anti-inflammatory efficacy of the developed drugs, even in advanced stage arthritis model. An immunological regulation mechanism study of PTT is first suggested in this study; the expression of the interleukin 22 receptor, implicated in the pathogenesis of arthritis, is downregulated in T lymphocytes by PTT, and Th17 differentiation from naïve CD4 T cell is inhibited. Collectively, inflammation-targeting MSCs conjugated with triamcinolone-loaded gold nanostar (Edu-MSCs-AuS-TA) promote the repolarization of macrophages and decrease neutrophil recruitment in joints. In addition, Edu-MSCs-AuS-TA significantly alleviate arthritis-associated pain, improve general locomotor activity, and more importantly, induce cartilage regeneration even for severe stages of arthritis model.

Phototherapy: A Conventional Approach to Overcome the Barriers in Oncology Therapeutics.

Cancer disease has outgrown a life-threatening disease. Having reference to preceding reports provided by the International Agency for Research on Cancer, an estimated 9.6 million deaths transpired from cancer worldwide in 2018. Similarly, about 18.1 million new cases of cancer are being reported. The rise in conventional treatments akin to surgeries, chemotherapies, and radiotherapies was enormously observed to eradicate cancer tumors. These studies have shown unfavorable side effects in clinical treatments. Drug resistivity and drug cytotoxicities are also major issues to overcome. Considering these, researchers are developing alternative methods that are robust, economical, and safe. The use of light for therapeutic purposes shows a great history in vitiligo treatment. The combination of an effective activating agent and phototherapy could result as the best alternative with a great outcome to minimize adverse effects on healthy tissues. The utilization of light in the deletion of tumors using photothermal agents, and photosensitizers, hence the phototherapies in oncology were discovered and rapidly involved in the advancement of clinical approach. Here, in this article, we tried to highlight the recent trends in phototherapy and reviewed different types of phototherapy methods in cancer treatments and their latest clinical, preclinical, and in vivo studies.

Photothermal Hydrogels for Promoting Infected Wound Healing.

Photothermal therapies (PTT), with spatiotemporally controllable antibacterial capabilities without inducing resistance, have shown encouraging prospects in the field of infected wound treatments. As an important platform for PTT, photothermal hydrogels exhibit attractive advantages in the field of infected wound treatment due to their excellent biochemical properties and have been intensively explored in recent years. This review summarizes the progress of the photothermal hydrogels for promoting infected wound healing. Three major elements of photothermal hydrogels, i.e., photothermal materials, hydrogel matrix, and construction methods, are introduced. Furthermore, different strategies of photothermal hydrogels in the treatment of infected wounds are summarized. Finally, the challenges and prospects in the clinical treatment of photothermal hydrogels are discussed.

DNA-Templated Ag@Pd Nanoclusters for NIR-II Photoacoustic Imaging-Guided Photothermal-Augmented Nanocatalytic Therapy.

Developing multifunctional nanozymes with photothermal-augmented enzyme-like reaction dynamics in the second near-infrared (NIR-II) biowindow is of significance for nanocatalytic therapy (NCT). Herein, DNA-templated Ag@Pd alloy nanoclusters (DNA-Ag@Pd NCs) are prepared as a kind of novel noble-metal alloy nanozymes by using cytosine-rich hairpin-shaped DNA structures as growth templates. DNA-Ag@Pd NCs exhibit high photothermal conversion efficiency (59.32%) under 1270 nm laser and photothermally augmented peroxidase-mimicking activity with synergetic enhancement between Ag and Pd. In addition, hairpin-shaped DNA structures on the surface of DNA-Ag@Pd NCs endow them with good stability and biocompatibility in vitro and in vivo, and enhanced permeability and retention effect at tumor sites. Upon intravenous injection, DNA-Ag@Pd NCs demonstrate high-contrast NIR-II photoacoustic imaging-guided efficient photothermal-augmented NCT of gastric cancer. This work provides a strategy to synthesize versatile noble-metal alloy nanozymes in a bioinspired way for highly efficient therapy of tumors.

Doxorubicin-Fe(III)-Gossypol Infinite Coordination Polymer@PDA:CuO2 Composite Nanoparticles for Cost-Effective Programmed Photothermal-Chemodynamic-Coordinated Dual Drug Chemotherapy Trimodal Synergistic Tumor Therapy.

To achieve the maximum therapeutic effects and minimize adverse effects of trimodal synergistic tumor therapies, a cost-effective programmed photothermal (PTT)-chemodynamic (CDT)-coordinated dual drug chemotherapy (CT) trimodal synergistic therapy strategy in chronological order is proposed. According to the status or volumes of the tumors, the intensity and time of each therapeutic modality are optimized, and three modalities are combined programmatically and work in chronological order. The optimal synergistic therapy begins with high-intensity PTT for 10 min to ablate larger tumors, followed by medium-intensity CDT for several hours to eliminate medium-sized tumors, and then low-intensity coordinated dual drugs CT lasts over 48 h to clear smaller residual tumors. Composite nanoparticles, made of Fe-coordinated polydopamine mixed with copper peroxide as the cores and their surface dotted with lots of doxorubicin-Fe(III)-gossypol infinite coordination polymers (ICPs), have been developed to implement the strategy. These composite nanoparticles show excellent synergistic effects with the minimum dose of therapeutic agents and result in nearly 100% tumor inhibition for mice bearing PC-3 tumors and no observed recurrence within 60 days of treatment. The ratios of the different therapeutic agents in the composite nanoparticles can be adjusted to accommodate different types of tumors with this cost-effective programmed trimodal therapy strategy.

The versatile family of molybdenum oxides: synthesis, properties, and recent applications.

The family of molybdenum oxides has numerous advantages that make them strong candidates for high-value research and various commercial applications. The variation of their multiple oxidation states allows their existence in a wide range of compositions and morphologies that converts them into highly versatile and tunable materials for incorporation into energy, electronics, optical, and biological systems. In this review, a survey is presented of the most general properties of molybdenum oxides including the crystalline structures and the physical properties, with emphasis on present issues and challenging scientific and technological aspects. A section is devoted to the thermodynamical properties and the most common preparation techniques. Then, recent applications are described, including photodetectors, thermoelectric devices, solar cells, photo-thermal therapies, gas sensors, and energy storage.

Second Near-Infrared Photothermal Semiconducting Polymer Nanoadjuvant for Enhanced Cancer Immunotherapy.

Immunotherapy has offered new treatment options for cancer; however, the therapeutic benefits are often modest and desired to be improved. A semiconducting polymer nanoadjuvant (SPNII R) with a photothermally triggered cargo release for second near-infrared (NIR-II) photothermal immunotherapy is reported here. SPNII R consists of a semiconducting polymer nanoparticle core as an NIR-II photothermal converter, which is doped with a toll-like receptor (TLR) agonist as an immunotherapy adjuvant and coated with a thermally responsive lipid shell. Upon NIR-II photoirradiation, SPNII R effectively generates heat not only to ablate tumors and induce immunogenic cell death (ICD), but also to melt the lipid layers for on-demand release of the TLR agonist. The combination of ICD and activation of TLR7/TLR8 enhances the maturation of dendritic cells, which amplifies anti-tumor immune responses. Thus, a single treatment of SPNII R-mediated NIR-II photothermal immunotherapy effectively inhibits growth of both primary and distant tumors and eliminates lung metastasis in a murine mouse model. This study thus provides a remote-controlled smart delivery system to synergize photomedicine with immunotherapy for enhanced cancer treatment.

Boosting Photothermal Theranostics via TICT and Molecular Motions for Photohyperthermia Therapy of Muscle-Invasive Bladder Cancer.

The development of photothermal agents with high photothermal conversion efficiency (PCE) can help to reduce drug and laser dosage, but still remains a big challenge. Herein, a novel approach is reported to design photothermal agents with high PCE values by promoting nonradiative heat generation processes through the cooperation of twisted intramolecular charge transfer (TICT) and molecular motions. Within the designed molecule 2DMTT-BBTD, the tetraphenylethenes act as molecular rotors, the long alkyl chain grafted thiophene helps to twist the molecular geometry to facilitate TICT state formation and preserve molecular motions in aggregate, while the strong electron-withdrawing BBTD unit enhances TICT effect. 2DMTT-BBTD exhibits NIR-absorption and a high PCE value of 74.8% under 808 nm laser irradiation. Gambogic acid (GA) which surmounts tumor cell thermotolerance by inhibiting heat shock protein 90 (HSP90) expression is coloaded into the nanoparticles, RGD peptide is further introduced to the nanoparticle surface to improve tumor accumulation. The resultant nanoparticles facilitate the effective low-temperature hyperthermia therapy of muscle-invasive bladder cancer (MIBC) with minimal damage to surrounding heathy tissues. This work delivers a new design concept for development of highly efficient photothermal agents, which also provides a safer approach for noninvasive treatment of MIBC and other malignant tumors.

In Vivo Regenerable Cerium Oxide Nanozyme-Loaded pH/H2O2-Responsive Nanovesicle for Tumor-Targeted Photothermal and Photodynamic Therapies.

Photodynamic therapy (PDT) and photothermal therapies (PTTs) are both promising strategies for effective tumor therapy. However, the absence of O2 at tumor sites hinders the sustained response of photosensitizers. Here, we develop a recycled cerium oxide (CeO2) catalase nanozyme-loaded hyaluronic acid nanovesicle to address the hypoxic tumor microenvironments and targeted delivery of the photosensitizers [indocyanine green (ICG)] to tumors. A polysaccharide complex effectively modifies the surface of a polyethylenimine phenylboronic acid nanostructure to achieve the CeO2 nanozyme-loading nanovesicles that exhibit both tumor-targeted enhancement and an improved hypoxic microenvironment. Also, the hydrogen peroxide responsiveness and acid-sensitive cleavage of phenylboronic acid specifically disintegrate the ICG/nanozyme coloaded nanovesicles in the tumor microenvironment. The in vitro synergistic tests and tumor suppression rate tests indicated that the cerium oxide nanozyme significantly improves the outcomes of PDT via cerium-element valence state recycling and hypoxia improvement, thus enhancing the tumor suppression efficiency. This pH/H2O2-responsive nanozyme/ICG codelivery system provides a good carrier model for improving the tumor microenvironment and increasing the efficiency of tumor-targeted PTT and PDT therapies.