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Graphical abstract Highlights • Ce6 was one-pot loaded on amine-functionalized IONCs through amide bonds. • PCM can quickly melt and release DOX once the temperature is over its melting point. • The heat generated by the IONCs upon NIR laser can execute the combined therapy. • The iron oxide nanocarriers can be employed as T 2 weighted MRI contrast agents. Abstract Combination therapy involves the design of one unit with various therapeutic effects, such as simultaneous photothermal therapy (PTT), chemotherapy and photodynamic therapy (PDT), to produce high therapeutic efficacy with minimized side effects. Here, we designed a single near-infrared (NIR) light induced tri-mode (PTT, PDT and chemotherapy) combined therapeutic nanoplatform (named IONCs@Ce6-DOX/PCM) based on amine-functionalized iron oxide nanocrystals (IONCs). The IONCs, were subsequently loaded with the photosensitizer chlorin e6 (Ce6), doxorubicin (DOX) and a layer of tetradecanol (PCM, a temperature sensitive phase-change material used as a smart switch for drug release). In this system, the IONCs generate heat for PTT and melt the coated PCM when irradiated by a 650 nm laser with a low power density (230 mW/cm2), resulting in the release of encapsulated DOX. Simultaneously, the exposed Ce6 can also generate cytotoxic reactive oxygen species (ROS) under the same NIR light irradiation, thereby achieving combined therapy triggered by a single light. Moreover, taking advantage of the magnetic property of IONCs, the nanoplatform could also be developed as a biocompatible diagnostic agent for magnetic resonance (MR) imaging. This, indicates that the multifunctional carriers can facilitate a range of imaging guided cancer treatments and provide synergistic photothermal/chemo/photodynamic therapy for improved treatment efficiency and minimized side effects. [ABSTRACT FROM AUTHOR]

[Display omitted] • The switch for treatment was only triggered under high heat conditions, allowing for human-controlled, on-demand treatment. • CaO 2 degraded in acidic TME, producing H 2 O 2 , O 2 and Ca(OH) 2 , which could improve and remodel TME. • Free Ca2+ accumulated in tumor cells and could initiate the process of calcium overload and calcification. • Calcification could play a role in inhibiting tumor growth and aiding CT imaging. The tumor microenvironment (TME) is complex in composition and unique in nature, and is closely related to the growth, invasion and metastasis of tumor cells. Improving and remodeling the TME to return it to a normalized state can fundamentally disrupt the environment and/or nutrient supply on which tumor cells depend. To achieve this goal, based on the unique physicochemical properties and biological effects of CaO 2 , we designed and constructed a Ca2+ nanogenerator (named as CaO 2 -Cu/ICG@PCM) that enables H 2 O 2 /O 2 self-supplementation and GSH depletion. The 808 nm laser induces the heat generation of photosensitizer indocyanine green (ICG) to initiate a series of reactions, followed by the production of copper ions, H 2 O 2 , O 2 and large amounts of Ca2+, which can eventually lead to the combined treatment of photodynamic therapy (PDT), chemodynamic therapy (CDT) and calcium overload. Additionally, the reaction process is accompanied by the generation of Ca(OH) 2 , which greatly improves the acidic environment of TME and effectively promotes the oxidation process of GSH by H 2 O 2 , achieving the purpose of remodeling TME. It is worth mentioning that a large amount of free Ca2+ accumulating in tumor cells can rapidly initiate the process of calcium overload and calcification, which can not only play a role in tumor suppression, but also assist CT imaging to detect the effect of treatment. Thus, CaO 2 -Cu/ICG@PCM could be a promising candidate for bioimaging and tumor therapy. [ABSTRACT FROM AUTHOR]

• Honeycomb MnO 2 with catalase-like activity can produce O 2 inside solid tumors. • The HA coating endowed the MCIH with the ability of actively targeted to the tumor site. • CuS nanoparticles and ICG molecules were loaded on with high loading rate (66.8% and 80.22%, respectively). • The released ICG and Mn2+ could be used for fluorescent imaging and T 1 -weighted MR imaging. The tumor microenvironment (TME) is the internal environment where tumor cells grow and develop. Constructing TME-activatable, specific imaging and treatment system is highly desired for accurate cancer diagnosis and therapy. Herein, by utilizing the degrading ability of honeycomb MnO 2 in the TME, a tumor-targeted and O 2 -evolving photothermal/photodynamic therapeutic nanoplatform with dual-modal imaging capability was designed and fabricated. In the structure, self-assembled MnO 2 was regarded as a carrier for cargo loading and O 2 production, and subsequently the CuS nanoparticles (NPs) and indocyanine green (ICG) molecules with ultra- high loading characteristics (CuS NPs could be loaded up to nearly 66.8% and ICG molecules could be loaded up to 80.22%) were loaded and further wrapped in hyaluronic acid (HA), endowing the system with the capability for specific interaction with CD44 over-expressed on tumor cells. Upon irradiation with 808 nm laser, the photothermal therapy (PTT) effects of the CuS NPs and ICG molecules would be triggered with satisfactory photostability. The degradation of the carrier could generate O 2 , thus solving the problem of hypoxia in the TME. Simultaneously, the released ICG molecules could also exert strong photodynamic therapy (PDT) effects when activated by the same light. Indeed, PTT and PDT are two kinds of light-mediated treatment. Moreover, the recovered fluorescence of the ICG molecules and the released Mn2+ resulted in excellent fluorescent imaging and T 1 -weighted MR imaging. An imaging directed synergistic phototherapy has thereby been realized. [ABSTRACT FROM AUTHOR]

The current conventional photo-therapeutic agents often show low therapy efficacy because of their single treatment model, the limited penetration depth of excitation light and hypoxia in the tumor microenvironment (TME). Herein, a new type of phthalocyanine manganese (MnPcE 4) photosensitizer with strong NIR absorption was designed and fabricated for the first time, and was used to modify pure Bi nanomaterials to obtain an intelligent multifunctional Bi/MnPcE 4 nanocomposites. The Mn2+ in the Bi/MnPcE 4 nanocomposite could catalyze H 2 O 2 to generate O 2 , thus helping to overcome TME hypoxia and enhancing the photodynamic therapy (PDT) efficacy. Further, the nanocomposites showed excellent T 1 -weighted MRI performance. Our novel use of a pure metal Bi core, offers lower toxicity, higher CT imaging performance, and a photothermal therapy (PTT) effect triggered by 808 nm near infrared (NIR) laser. Moreover, in vivo fluorescence imaging (in vivo FL) vividly showed that the nanocomposite rapidly accumulates in tumor sites due to the enhanced permeability and retention (EPR) effect and metabolized in the organs. The presence of Bi enables the use of these nanocomposites as a CT contrast agent, and the Mn content enables them to be used in MRI. This triple imaging ability implies that our nanocomposites have a high potential for use in imaging directed tumor therapy. Image 1 [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • CuS nanoparticles and g-C 3 N 4 QDs endow the nanoplatform with tumor microenvironment-responsive PTT and PDT functions. • The targeting agent FA allows the nanoplatform to specifically act on cancer cells and has no damage to healthy tissues. • 808 nm NIR excitation light does not cause overheating of tissues compared to 980 nm NIR light. • The doping of rare earth ions makes the nanoplatform have triple UCL, CT, and MRI imaging. Abstract Combined therapy with multimodal therapeutic agents based on nanomaterials has been shown as a promising approach to cancer treatment. In this report, a highly efficient multifunctional anti-cancer nanocomposite was fabricated by assembling a photothermal agent (CuS nanoparticles) and a photodynamic agent (g-C 3 N 4 quantum dots) on upconversion nanoparticles (UCNPs) after mesoporous silica coating. Then, the surface modification of the obtained nanocomposite (abbreviated as CUSCs) with polyethylene glycol (PEG) and folic acid (FA) endows the final sample (denoted as CUSCs-PEG-FA) with an excellent cancer cell targeting effect and biocompatibility. In this nanoplatform, CuS nanoparticles are an inorganic substance with low toxicity and high photothermal conversion efficiency. g-C 3 N 4 QDs have excellent biocompatibility and are beneficial for cellular uptake due to their small size. UCNPs can be excited by near-infrared (NIR) light to produce ultraviolet and visible (UV– vis) light emission, which overlaps with the UV absorption peak of high fluorescence g-C 3 N 4 quantum dots (QDs). Therefore, when the nanocomposite is excited by 808 nm NIR light, a synergistic treatment effect will be presented. Since the wavelengths absorbed by the chosen photothermal agent and the photosensitizer are different, sufficient utilization of energy can be achieved. Combining photothermal therapy (high photothermal conversion efficiency of 27.4%) and photodynamic therapy can inhibit cancer more effectively compared to any monotherapy. Moreover, as a result of the inherent performance ability of the doped rare earth ions, excellent applicability for computed tomography (CT), upconversion luminescence (UCL) and magnetic resonance imaging (MRI) has been achieved. [ABSTRACT FROM AUTHOR]

Graphical abstract Under the NIR irradiation, FMUP can generate PCT and PDT synergistic effect to cure cancer after FMUP have been swallowed into tumour cells. Highlights • MIL-100(Fe) coated on Fe 3 O 4 followed by linking upconversion nanoparticles formed a heterojunction photosensitizer. • The heterojunction structure in the interface markedly enhanced the OH production capability. • The synergistic photodynamic and photochemo-therapy greatly improved the efficiency. • The computed tomography (CT) and up-conversion luminescence imaging realized a potential imaging-guided therapy. Abstract Currently, photodynamic therapy (PDT) has been greatly restricted by the tumor hypoxia. To overcome this problem, here, we designed a novel nanoplatform, Fe 3 O 4 @MIL-100(Fe)-UCNPs (abbreviated as FMU), in which UCNPs were acted as energy transducers to transfer NIR-UV/vis light to the heterojunction photosensitizer Fe 3 O 4 @MIL-100(Fe) (abbreviated as FM), producing cytotoxic hydroxyl radicals (OH) with a high tumor cell oxidation capability independent of tumor oxygen. In particular, the recombination of electrons and holes has been markedly inhibited due to the formation of heterojunctions in the interfaces between MIL-100(Fe) and Fe 3 O 4 nanoparticles, thus greatly enhancing the capability for OH production. Meanwhile, the Fe3+/Fe2+ ions were used to provide the photochemotherapy (PCT) effect based on the photo-Fenton reaction, thereby achieving combined PDT and PCT synergistic therapy. The outstanding antitumor efficiency was verified by in vivo and in vitro assays, and it was shown that the therapeutic process can be monitored by computed tomography (CT) and upconversion luminescence (UCL) imaging, suggesting that the resultant nanoplatform has potential for use in imaging-guided cancer therapy. [ABSTRACT FROM AUTHOR]

Thiol capped gold nanoparticles with small size, high dispersity, and broad light absorption covering ultraviolet (UV) to near infrared (NIR) region have been developed for catalysis, fluorescence imaging and photodynamic therapy (PDT). The constitution of the metal core in such nanoparticles can strongly influence the luminescence, catalysis, and stability properties. However, to date, a corresponding investigation of the influence of the metallic core on the generation of reaction oxygen species (ROS) and its therapeutic efficiency towards tumor cells remains to be lacking. Herein, we fabricated bimetallic nanoparticles by introducing bismuth into captopril capped gold nanoparticles. Surprisingly, the introduction of the Bi was found enhance the photothermal effect of the nanoparticles to a great extent, and the variation trends for the thermal effect, ROS generation rate, and tumor cell inhibition effect were found to disparate with the changes in the Au and Bi composition. The origin of the photothermal effect was deduced through density functional theory calculations based on microscopic construction. Combined with the intrinsic photodynamic effect, the bimetallic nanoparticles showed an outstanding tumor cell inhibition effect. Furthermore, due to the excellent CT imaging property, our designed nanoparticles provide the exciting possibility to realize CT imaging guided and light-mediated tumor therapy. Image 1 [ABSTRACT FROM AUTHOR]

• The smart nanoplatform LDH_ZnPcG 4 -FA/DOX was constructed by co-precipitation method. • With NIR irradiation, LDH_ZnPcG 4 -FA/DOX showed excellent antitumor performance in vivo. • The ZnPcG 4 -FA and DOX could be released from LDH_ZnPcG 4 -FA/DOX in acidic TME. • LDH_ZnPcG 4 -FA/DOX could be used as an agent for TME-responsive imaging. Designing a phototherapeutic material that simultaneously has target, tumor microenvironment (TME)-response, high-quality imaging and synergistic therapy has attracted much attention in anticancer field. Herein, a novel stimuli-responsive multifunctional nanoplatform has been constructed by inserting folic acid linked ZnPcG 4 molecules (ZnPcG 4 -FA) into layered double hydroxides (LDH) by a facile co-precipitation method. Subsequently, chemotherapeutic drug (doxorubicin hydrochloride, DOX) was loaded on the surface of LDH (named as LDH_ZnPcG 4 -FA/DOX), which can be released in a controlled and targeted manner with the degradation of LDH in the acidic TME. Upon the 650 nm laser irradiation, this nanoplatform demonstrated excellent anticancer efficiency in vitro and in vivo due to the synergistic chemo-photodynamic therapy derived from the released DOX and ZnPcG 4 photosensitizer (PS). Interestingly, the luminescent ZnPcG 4 -FA in LDH_ZnPcG 4 -FA/DOX exhibited low fluorescence in a neutral environment, while recovered strong fluorescence with the degradation of LDH and release of DOX in acidic TME, implying its TME-responsive imaging property. Besides, in vivo fluorescence imaging of LDH_ZnPcG 4 -FA/DOX represent that the nanoplatform has higher selectivity to tumor cells than normal cells. This study contributes to design a kind of smart "all-in-one" nanoplatform to realize imaging guided synergistic therapy. [ABSTRACT FROM AUTHOR]

• For the first time, ultrathin BP nanosheets and CuS nanoparticles are integrated into one system. • The great specific surface area of BP and the pore size of mesoporous silica are favorable for high DOX loading capacity. • The extent of drug release can be detected based on the reduction in the red/green (R/G) ratio elicited by DOX release. • Doping of rare earth ions imparts imaging-guided photodynamic/photothermal/chemo-synergistic treatment. The strategy of combining imaging and treatment has been shown as a widely studied and promising approach. In this work, we first integrated copper sulfide (CuS) nanoparticles and black phosphorus (BP) nanosheets with strong negative charges via mesoporous silica-coated upconversion nanoparticles (UCNPs). Synergistic treatment of photothermal, photodynamic and chemotherapy can be achieved after loading doxorubicin (DOX). The nanocomposites perform excellent antitumor efficiency under 808 nm near-infrared (NIR) light, and avoid the slightly lower efficiency and limited penetration depth of conventional ultraviolet and visible (UV– vis) light. In this system, the pore size of mesoporous silica and the large specific surface area of BP are advantageous for achieving high DOX loading capacity. Furthermore, the reduction in the red/green (R/G) ratio elicited by DOX release can be employed to determine the extent of DOX release by the fluorescence resonance energy transfer (FRET) process. CT/MR imaging induced by doping of rare earth ions imparts multimode imaging capabilities to nanosystem under 808 nm light irradiation, thereby enabling imaging-guided cancer treatment. [ABSTRACT FROM AUTHOR]