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Porphyrins and their derivatives are widely used as photosensitizers and sonosensitizers in tumor treatment. Nevertheless, their poor water solubility and low chemical stability reduce their singlet oxygen ( 1 O 2 ) yield and, consequently, their photodynamic therapy (PDT) and sonodynamic therapy (SDT) efficiency. Although strategies for porphyrin molecule assembly have been developed to augment 1 O 2 generation, there is scope for further improving PDT and SDT efficiencies. Herein, we synthesized ordered manganese porphyrin (SM) nanoparticles with well-defined self-assembled metalloporphyrin networks that enabled efficient energy transfer for enhanced photocatalytic and sonocatalytic activity in 1 O 2 production. Subsequently, Au nanoparticles were grown in situ on the SM surface by anchoring the terminal alkynyl of porphyrin to form plasmonic SMA heterostructures, which showed the excellent near-infrared-II (NIR-II) region absorption and photothermal properties, and facilitated electron-hole pair separation and transfer. With the modification of hyaluronic acid (HA), SMAH heterostructure nanocomposites exhibited good water solubility and were actively targeted to cancer cells. Under NIR-II light and ultrasound (US) irradiation, the SMAH generates hyperthermia, and a large amount of 1 O 2 , inducing cancer cell damage. Both in vitro and in vivo studies confirmed that the SMAH nanocomposites effectively suppressed tumor growth by decreasing GSH levels in SDT-augmented PDT/PTT. Moreover, by utilizing the strong absorption in the NIR-II window, SMAH nanocomposites can achieve NIR-II photoacoustic imaging-guided combined cancer treatment. This work provides a paradigm for enhancing the 1 O 2 yield of metalloporphyrins to improve the synergistic therapeutic effect of SDT/PDT/PTT.

Bismuth sulfide is widely used as an n-type semiconductor material in photocatalytic reactions. However, bismuth sulfide has poor absorption in the near-infrared region and low charge separation efficiency, limiting its application in phototherapy and sonodynamic therapy (SDT). In this study, we successfully synthesized an "all-in-one" phototheranostic nanoplatform, namely Bi 2 S 3-x -Au@HA, based on a single second near-infrared (NIR-II) light-responsive Schottky-type Bi 2 S 3-x -Au heterostructure for photoacoustic (PA) imaging-guided SDT-enhanced photodynamic therapy (PDT)/photothermal therapy (PTT). Bi 2 S 3-x -Au@HA exhibits excellent NIR-II plasmonic and photothermal properties, rendering it with NIR-II PA imaging capabilities for accurate diagnosis. Additionally, the high-density sulfur vacancies constructed on the Bi 2 S 3 surface cause it to possess a reduced band gap (1.21 eV) that can act as an electron trap. Using the density functional theory, we confirmed that the light and ultrasound-induced electrons are more likely to aggregate on the Au nanoparticle surface through interfacial self-assembly, which promotes electron-hole separation and enhances photocatalytic activity with increased reactive oxygen species (ROS) generation. With a further modification of hyaluronic acid (HA), Bi 2 S 3-x -Au@HA can selectively target cancer cells through HA and CD44 protein interactions. Both in vitro and in vivo experiments demonstrated that Bi 2 S 3-x -Au@HA effectively suppressed tumor growth through SDT-enhanced PTT/PDT under a single NIR-II laser and ultrasound irradiation with negligible toxicity. Our findings provide a framework for fabricating Schottky-type heterostructures as single NIR-II light-responsive nanotheranostic agents for PA imaging-guided cancer phototherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Metal complexes have shown promise as photosensitizers for cancer diagnosis and therapeutics. However, the vast majority of metal photosensitizers are not ideal and associated with several limitations including pharmacokinetic limitations, off-target toxicity, fast systemic clearance, poor membrane permeability, and hypoxic tumour microenvironments. Metal complex functionalized nanomaterials have the potential to construct multifunctional systems, which not only overcome the above defects of metal complexes but are also conducive to modulating the tumour microenvironment (TME) and employing combination therapies to boost photodynamic therapy (PDT) efficacy. In this review, we first introduce the current challenges of photodynamic therapy and summarize the recent research strategies (such as metal coordination bonds, self-assembly, π-π stacking, physisorption, and so on) used for preparing metal complexes functionalized nanomaterials in the application of PDT.

Natural biopolymers can be controllably in situ synthesized in organisms and play important roles in biological activities. Inspired by this, the manipulation of in situ biosynthesis of functional polymers in vivo will be an important way to obtain materials for meeting biological requirements. Herein, in situ biosynthesis of functional conjugated polymer at the tumor site was achieved via the utilization of specific tumor microenvironment (TME) characteristics for the first time. Specially, a water-soluble aniline dimer derivative ( N -(3-sulfopropyl) p -aminodiphenylamine, SPA) was artfully in situ polymerized into polySPA (PSPA) nanoparticles at the tumor site, which was activated via the catalysis of hydrogen peroxide (H 2 O 2 ) overexpressed in TME to produce hydroxyl radical (•OH) by coinjected horseradish peroxidase (HRP). Benefiting from outstanding near-infrared (NIR)-II absorption of PSPA, the in situ polymerization process can be validly monitored by photoacoustic (PA) signal at the NIR-II region. Meanwhile, in situ polymerization would induce the size of polymeric materials from small to large, improving the distribution and retention of PSPA at the tumor site. On the combination of NIR-II absorption of PSPA and the size variation induced by polymerization, such polymerization can be applied for tumor-specific NIR-II light mediated PA image and photothermal inhibition of tumors, enhancing the precision and efficacy of tumor phototheranostics. Therefore, the present work opens the way to manipulate TME-activated in situ biosynthesis of functional conjugated polymer at the tumor site for overcoming formidable challenges in tumor theranostics.

Mitochondrial sulfur dioxide (SO 2 ) correlates with various activities of the development and progression of cancer. However, the specific biological function of mitochondrial SO 2 in cancerous cells remains amphibolous. Therefore, it is of great significance and urgency to develop a rapid and accurate method to monitor the dynamic fluctuations of mitochondrial SO 2 in cancer cells and tumor tissue. Herein, in this work, we introduce a "dual-positive charges" strategy for simultaneously enhancing the sensitivity and mitochondrial targeting ability of SO 2 detection in cancer cells for the first time. For proof of concept, the dual positive charged probe DCP was rationally designed and synthesized based on chromenoquinoline fluorophore. Correspondingly, we also synthesized single positive charged SO 2 probe MCP as controls. As expected, the detection limit of dual positive charged DCP for SO 2 detection was 0.06 μM, which was 7-fold lower than that of the single positive charged probe MCP. Besides, DCP showed a higher mitochondrial co-localization coefficient in cancer cells and it could distinguish cancer cells (HeLa) and normal cells (L929) in co-incubated system. In a word, the evidence suggested that the implementation of dual-positive charges strategy greatly improved the sensitivity to SO 2 response and the specificity of mitochondrial targeting in cancer cells. Finally, DCP was successfully applied to monitor SO 2 fluctuation in cancer cells, tumor tissue and living zebrafish. Thus, this work provides a powerful tool to investigate the role of mitochondrial SO 2 in cancer and other related diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Specific tumor-responsive capabilities and efficient synergistic therapeutic performance are the keys to effective tumor treatment. Herein, AuNRs@SiO 2 -RB@MnO 2 was developed as a new type of tumor-responsive nanotheranostic for multimodal imaging and synergistic chemodynamic/photothermal therapy. In AuNRs@SiO 2 -RB@MnO 2 , the SiO 2 layer wraps the AuNRs, providing light absorption in the second near-infrared (NIR-II) region. The SiO 2 layer also adsorbs the MnO 2 nanosheets, which have Fenton-like activity, resulting in a fluorescent sensing platform based on the fluorescence quenching properties of MnO 2 for rhodamine B dye. The fluorescence can be recovered by the consumption of MnO 2 by glutathione, which simultaneously produces Mn 2+ in the tumor region. The recovery of fluorescence reflects the consumption of glutathione and the increase in Mn 2+ , which produces hydroxyl radicals via Fenton-like reaction in the tumor microenvironment to realize chemodynamic therapy. Meanwhile, the AuNRs are a good photothermal reagent that can effectively absorb NIR-II light and convert it into heat energy to kill tumor cells via photothermal therapy. The NIR-II absorption performance of the AuNRs provides good photoacoustic imaging and deep photothermal performance, which is favorable for efficient NIR-II photoacoustic imaging-guided photothermal therapy. As a result, the AuNRs@SiO 2 -RB@MnO 2 nanotheranostic exhibits outstanding imaging and synergistic chemodynamic/photothermal therapeutic performance for tumor imaging and treatment.

The therapeutic effect of photothermal therapy (PTT) and photodynamic therapy (PDT) is severely limited because of the shallow tissue penetration depth of the first near-infrared (NIR-I) light. Multifunctional nanotheranostics irradiated by the second near-infrared (NIR-II) light have received wide interest with respect to deeper tissue penetration, and sonodynamic therapy (SDT) synergistic phototherapy can achieve the complete elimination of tumors. Herein, we successfully constructed a single NIR-II light-induced nanotheranostic using cerium oxide (CeO 2- x ) with abundant oxygen vacancies for photoacoustic imaging-guided SDT-enhanced phototherapy for the first time. CeO 2- x with surface crystalline disorder showed extensive NIR-II region absorption and an outstanding photothermal conversion ability. In addition, the CeO 2- x layer with numerous oxygen defects can promote the separation of holes and electrons by ultrasound irradiation, which can remarkably enhance the efficacy of phototherapy to achieve high-efficiency tumor ablation. CeO 2- x was surface modified with hyaluronic acid (HA) to prepare CeO 2- x @HA to allow active tumor targeting efficiency. Both cell and animal experiments confirmed that all-in-one CeO 2- x @HA exhibited a high therapeutic efficacy of SDT-enhanced PDT/PTT under 1064 nm laser irradiation, which achieved complete tumor eradication without systemic toxicity. This study significantly broadened the application of NIR-II-responsive CeO 2- x for photoacoustic imaging-mediated SDT-enhanced phototherapy to the highly efficient and precise elimination of tumors.

Phototheranostic offers a regional-focused tumor treatment upon photoirradiation. However, it is difficult to completely eradicate solid tumors using a conventional phototheranostic owing to the residual tumor cells outside the laser irradiation range. Herein, we fabricated a metallopolysaccharide-based smart nanotheranostic (Fe- d HA) via a nanoassembly-driven method, in which Fe 3+ ions were coordinated to dopamine-modified biopolysaccharide hyaluronic acid ( d HA). Taking advantage of the structural backbone and intrinsic dual-information-related functions of HA as well as the bi-functional Fe(III)-coordination centers, Fe- d HA can efficiently target tumor cells for phototheranostic. Additionally, it can be activated by endogenous overexpressed hyaluronidase to achieve sequential ferroptosis in tumor cells. The precise imaging and effective tumor inhibition using this metallopolysaccharide-based nanotheranostic were significantly demonstrated in vivo and in vitro. Thus, this rationally designed Fe- d HA provided a simple metallopolysaccharide strategy to develop an "all-in-one" smart nanotheranostic to synergize different therapeutic modalities for improving cancer therapy.

Phototherapy, a type of photoresponsive regulation of biological activities, together with additional stimuli-responsive features, offers significant potential for enhancing the precision and efficacy of cancer treatments. To achieve tumor-specific therapeutics, numerous studies have focused on the development of smart phototherapeutic nanomaterials (PNMs) that can respond to endogenous pathological characteristics (e. g., mild acidity, the overproduction of glutathione, the overproduction of hydrogen peroxide, the overexpression of specific surface receptors, etc.) present in the tumor and/or exogenous stimuli. Such responsiveness can effectively improve the physicochemical properties, cellular uptake, tumor-targeting performance, and pharmacokinetic profile of PNMs. Herein, we will systematically discuss recent advances in this field. Moreover, potential challenges and future directions in the development of stimuli-responsive PNMs are also presented to support the development of this emerging cutting-edge research area., (© 2020 Wiley-VCH GmbH.)

The integration of surface-enhanced Raman spectrum (SERS) and fluorescence-photoacoustic multimodal imaging in near-infrared photothermal therapy is highly desirable for cancer theranostic. However, typically, gold nanotheranostics usually require an additional modification of fluorophores and complex design refinements. In this work, by integrating surface-modified cysteine-hydroxyl merocyanine (CyHMC) molecules onto AuNRs, a novel lysosome-targeted gold-based nanotheranostics AuNRs-CyHMC that combines the specificity of Raman spectrum, the speed of fluorescence imaging, and deep penetration of photoacoustic imaging was successfully fabricated. Interestingly, fluorescence and Raman signals in this AuNRs-CyHMC system do not interfere, but it has pH-sensitive Raman signals and self-fluorescence localization ability under different excitation wavelengths. Fluorescence co-localization experiments further confirmed the lysosome-targeting ability of AuNRs-CyHMC. Typically, the proposed nanotheranostics were capable of SERS monitoring pH changes in both phosphate-buffered saline and living cells. Meanwhile, in vitro and in vivo experiments revealed that AuNRs-CyHMC possessed excellent fluorescence-photoacoustic performance and could be used for multimodal imaging-guided photothermal therapy. Furthermore, our work implied that gold nanotheranostics can provide great potential for cancer diagnosis and treatment.

Second near-infrared (NIR-II) window responsive phototheranostic agents have a precise spatiotemporal potential for the diagnosis and treatment of cancer. In this study, a full-spectrum responsive ZrO 2 -based phototheranostic agent was found to achieve NIR-II photoacoustic (PA) imaging-guided tumour-targeting phototherapy. Initially, the ZrO 2 -based phototheranostic agent was fabricated through NaBH 4 reduction to form boron-doped oxygen-deficient zirconia (ZrO 2-x -B), an amino-functionalised SiO 2 shell and a further covalent connection with hyaluronic acid (HA), namely, ZrO 2-x -B@SiO 2 -HA. In the ZrO 2-x -B@SiO 2 -HA system, the oxygen vacancy and boron doping resulted in full-spectrum absorption, enabling a high NIR-II photothermal conversion, high-resolution PA imaging ability and a remarkable production of reactive oxygen species (ROS). The surface modification of HA provided ZrO 2-x -B@SiO 2 -HA with water dispersibility and a targeting capability for CD44 overexpressed cancer cells. Furthermore, in vitro and in vivo experiments showed that NIR-II activated ZrO 2-x -B@SiO 2 -HA had a targeted photothermal/photodynamic effect for cancer elimination under the real-time guidance of NIR-II PAs. Hence, ZrO 2-x -B@SiO 2 -HA displays a precise NIR-II radiation-activated phototheranostic potential for PA imaging-guided cancer-targeting photothermal/photodynamic therapy.

Although phototherapy has been considered as an emerging and promising technology for cancer therapy, its therapeutic specificity and efficacy are severely limited by nonspecific uptake by normal tissues, tumor hypoxia, and so on. Herein, combination-responsive strategy (CRS) is applied to develop one kind of hyaluronic acid-hybridized Ru nanoaggregates (HA-Ru NAs) for enhanced cancer phototherapy via the reasonable integration of receptor-mediated targeting (RMT) and tumor-microenvironment responsiveness (TMR). In this nanosystem, the HA component endows HA-Ru NAs with RMT characteristic to selectively recognize CD44-overexpressing cancer cells, whereas the Ru nanocomponent makes HA-Ru NAs have TMR therapy activity. Specially, the Ru nanocomponent not only has near-infrared-mediated photothermal and photodynamic functions but also can catalyze H 2 O 2 in tumor tissue to produce O 2 for the alleviation of tumor hypoxia and toxic •OH for chemodynamic therapy. Benefitting from these, HA-Ru NAs can be considered as a promising kind of CRS nanoplatforms for synergistic photothermal/photodynamic/chemodynamic therapies of cancer, which will not only effectively improve the phototherapeutic specificity and efficacy but also simplify the therapeutic nanosystems. Meanwhile, HA-Ru NAs can serve as a photoacoustic and computed tomography imaging contrast agent to monitor tumors. Such CRS nanoplatforms hold significant potential in improving therapeutic specificity and efficacy for enhanced cancer phototheranostics.

Carbon nanomaterials have received great attention from the scientific community over the past few decades because of their unique physical and chemical properties. In this minireview, we will summarize the recent progress of the use of various carbon nanomaterials in the field of cancer phototherapy. The structural characteristics of each category and the surface functionalization strategies of these nanomaterials will be briefly introduced before focusing on their therapeutic applications. Recent advances on their use in photothermal therapy, photodynamic therapy, and combined phototherapies are presented. Moreover, a few challenges and perspectives on the development of carbon nanomaterials for future theranostics are also discussed., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)