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Thermoelectric therapy has emerged as a promising treatment strategy for oncology, but it is still limited by the low thermoelectric catalytic efficiency at human body temperature and the inevitable tumor thermotolerance. We present a photothermoelectric therapy (PTET) strategy based on triphenylphosphine-functionalized Cu 3 VS 4 nanoparticles (CVS NPs) with high copper ionic mobility at room temperature. Under near-infrared laser irradiation, CVS NPs not only generate hyperthermia to ablate tumor cells but also catalytically yield superoxide radicals and induce endogenous NADH oxidation through the Seebeck effect. Notably, CVS NPs can accumulate inside mitochondria and deplete NADH, reducing ATP synthesis by competitively inhibiting the function of complex I, thereby down-regulating the expression of heat shock proteins to relieve tumor thermotolerance. Both in vitro and in vivo results show notable tumor suppression efficacy, indicating that the concept of integrating PTET and mitochondrial metabolism modulation is highly feasible and offers a translational promise for realizing precise and efficient cancer treatment.

Arming activatable mild-photothermal therapy (PTT) with the property of relieving tumor thermotolerance holds great promise for overcoming traditional mild PTT limitations such as thermoresistance, insufficient therapeutic effect, and off-target heating. Herein, a mitochondria-targeting, defect-engineered AFCT nanozyme with enhanced multi-enzymatic activity was elaborately designed as a tumor microenvironment (TME)-activatable phototheranostic agent to achieve remarkable anti-tumor therapy via "electron transport chain (ETC) interference and synergistic adjuvant therapy". Density functional theory calculations revealed that the synergistic effect among multi-enzyme active centers endows the AFCT nanozymes with excellent catalytic activity. In TME, open sources of H 2 O 2 can be achieved by superoxide dismutase-mimicking AFCT nanozymes. In response to the dual stimuli of H 2 O 2 and mild acidity, the peroxidase-mimicking activity of AFCT nanozymes not only catalyzes the accumulation of H 2 O 2 to generate ·OH but also converts the loaded 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) into its oxidized form with strong near-infrared absorption, specifically unlocking its photothermal and photoacoustic imaging properties. Intriguingly, the undesired thermoresistance of tumor cells can be greatly alleviated owing to the reduced expression of heat shock proteins enabled by NADH POD-mimicking AFCT-mediated NADH depletion and consequent restriction of ATP supply. Meanwhile, the accumulated ·OH can facilitate both apoptosis and ferroptosis in tumor cells, resulting in synergistic therapeutic outcomes in combination with TME-activated mild PTT.

As the least toxic heavy metal, monoelemental bismuth nanomaterials with several superiorities are the ideal theranostic agents. However, bismuth nanoparticles are easily oxidized by oxygen in air or media, limiting their clinical application. In contrast, the oxidization of Bi 0 to Bi 3+ can activate the chemodynamic therapy (CDT) by transferring endogenous H 2 O 2 into • OH. Herein, a well-designed Bi-DMSNs@PCM nanosystem was prepared via in situ growth of Bi nanodots and a coating of phase-change material (PCM) on the surface of dendritic mesoporous silica nanoparticles (DMSNs). The coated PCM protects the Bi nanodots from oxidation by keeping them in the Bi 0 state for more than 15 d. When irradiated using the near infrared-II (NIR-II) laser with a low power density (0.5 W/cm 2 ), the heat generated from the Bi nanodots melts the PCM shell to trigger CDT through a Fenton-like reaction, accompanied by heat-induced photothermal therapy (PTT). Notably, the CDT can also compensate for the reduced PTT effect caused by the oxidation of Bi nanodots, and a satisfactory treatment effect is realized. Additionally, photoacoustic and computed tomography imaging properties were obtained. Our strategy transfers the detrimental self-oxidation of bismuth to a beneficial therapeutic mode, enhancing the potential of Bi for clinical use.

The construction of nanoplatforms with combined photothermal properties and cascading enzymatic activities has become an active area of anticancer research. However, the overheating of photothermal therapy (PTT) and the specific properties of tumor microenvironment (TME) greatly impaired the therapeutic efficiency. Herein, we rationally fabricated a virus-like SiO x /CeO 2 /VO x (SCV) nanoplatform for 1064 nm near-infrared (NIR) triggered mild-temperature PTT and nanozyme catalytic therapy. Firstly, the virus-like shape of SiO x /CeO 2 /VO x made it favorable for cell adhesion and improved its phagocytosis in cells, and the SCV generated an effective PTT effect upon 1064 nm laser irradiation. Particularly, the produced VO 2+ in TME could be used as a heat shock protein inhibitor to inhibit the expression of heat shock protein 60 (HSP60) to enhance the PTT efficiency. Moreover, the SCV nanozyme exhibited obvious peroxidase-mimic (POD) catalytic activity, which could generate highly toxic free radical ions (˙OH) under acidic conditions. The mild-temperature heat and ˙OH produced by enzymatic catalysis effectively blocked the tumor growth, as verified firmly by in vitro and in vivo tests. Our designed virus-like SCV nanozyme with POD mimic enzyme activity and a mild photothermal effect may provide a new way of thinking about the combination therapy model.

Mitochondria are the "power plant" of the cell, providing a constant source of energy, and are involved in a variety of intracellular signaling pathways. Among these pathways, Ca 2+ homeostasis is closely related to the normal function of mitochondria. By destroying the Ca 2+ steady state of mitochondria and disrupting their multiple cellular activities, tumor cell killing can be achieved. In addition, the presence of an intracellular oxidative stress state triggers the closure of cellular calcium channels, which leads to intracellular Ca 2+ retention and enrichment. We designed a targeted and tumor microenvironment (TME)-responsive CaO 2 -based nanosystem that can selectively target cancer cells for pH-controlled degradation and drug release, alter cellular physiological mechanisms by disrupting Ca 2+ homeostasis in an artificial manner, and introduce mitochondrial Ca 2+ excess-mediated apoptosis. Meanwhile, the production of Ca(OH) 2 will raise the pH of the microenvironment and subsequently promote the oxidation process of glutathione by H 2 O 2 released from CaO 2 degradation, achieving the goal of remodeling TME. Moreover, calcium overload of tumor cells and calcification of tissues can both inhibit tumor growth and act as a contrast agent for computed tomography imaging.

The development of near-infrared (NIR) laser triggered phototheranostics for multimodal imaging-guided combination therapy is highly desirable. However, multiple laser sources, as well as inadequate therapeutic efficacy, impede the application of phototheranostics. Here, we develop an all-in-one theranostic nanoagent PEGylated DCNP@DMSN-MoO x NPs (DCDMs) with a flower-like structure fabricated by coating uniformly sized down-conversion nanoparticles (DCNPs) with dendritic mesoporous silica (DMSN) and then loading the ultrasmall oxygen-deficient molybdenum oxide nanoparticles (MoO x NPs) inside through an electrostatic interaction. Owing to the doping of Nd ions, when excited by an 808 nm laser, DCNPs emit bright NIR-II emissions (1060 and 1300 nm), which have characteristic high spatial resolution and deep tissue penetration. In terms of treatment, MoO x NPs could be specifically activated by excessive hydrogen peroxide (H 2 O 2 ) in the tumor microenvironment, thus generating 1 O 2 via the Russell mechanism. In addition, the excessive glutathione (GSH) in the tumor cells could be depleted through the Mo-mediated redox reaction, thus effectively decreasing the antioxidant capacity of tumor cells. Importantly, the excellent photothermal properties (photothermal conversion efficiency of 51.5% under an 808 nm laser) synergistically accelerate the generation of 1 O 2 . This cyclic redox reaction of molybdenum indeed ensured the high efficacy of tumor-specific therapy, leaving the normal tissues unharmed. MoO x NPs could also efficiently catalyze tumor endogenous H 2 O 2 into a considerable amount of O 2 in an acidic tumor microenvironment, thus relieving hypoxia in tumor tissues. Moreover, the computed tomography (CT) and T 1 -weighted magnetic resonance imaging (MRI) effect from Gd 3+ and Y 3+ ions make DCNPs act as a hybrid imaging agent, allowing comprehensive analysis of tumor lesions. Both in vitro and in vivo experiments validate that such an "all-in-one" nanoplatform possesses desirable anticancer abilities under single laser source irradiation, benefiting from the NIR-II fluorescence/CT/MR multimodal imaging-guided photothermal/chemodynamic synergistic therapy. Overall, our strategy paves the way to explore other noninvasive cancer phototheranostics.

The development of a stimulus-responsive nanosystem provides an effective method for improving the accuracy and efficiency of chemotherapy. Meanwhile, traditional photodynamic therapy (PDT) has been substantially restricted by the low dosage of photosensitizer and limited penetration depth of the ultraviolet (UV) or visible light used for excitation. Here, we designed a smart multifunctional nanoplatform by coating core-shell composite mesoporous silica-encapsulated upconversion nanoparticles and chlorin e6 (Ce6) with degradable calcium phosphate, followed by the loading of doxorubicin (DOX). In our structure, the as-synthesized nanoplatform exhibits high responsiveness to a low pH value and degrades rapidly in the weakly acidic tumor microenvironment, allowing the quick release of loaded DOX in tumor sites. Interestingly, the loaded DOX, whose release depends on the pH value and positively correlates with the calcium-ion concentration, enables drug release to be monitored in real time. Combined with photosensitizer Ce6-induced PDT triggered by an 808 nm near-infrared light, synergistic chemo-photodynamic therapy is achieved, thus leading to a highly efficient anticancer treatment in vitro and in vivo. Importantly, the inherent properties of rare earth ions (Gd 3+ , Yb 3+ , and Nd 3+ ) make the nanoplatform possess UCL, MRI, and CT trimode imaging capabilities, thus achieving a multiple imaging modality-guided synergistic therapy.