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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, Ca2+ homeostasis is closely related to the normal function of mitochondria. By destroying the Ca2+ 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 Ca2+ retention and enrichment. We designed a targeted and tumor microenvironment (TME)-responsive CaO2-based nanosystem that can selectively target cancer cells for pH-controlled degradation and drug release, alter cellular physiological mechanisms by disrupting Ca2+ homeostasis in an artificial manner, and introduce mitochondrial Ca2+ 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 H2O2 released from CaO2 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 endogenous tumor microenvironment (TME) can signally influence the therapeutic effects of cancer, so it is necessary to explore effective synergistic therapeutic strategies based on changing of the TME. Here, a catalytic cascade nanoplatform based on manganese (Mn)-etched dendritic mesoporous silicon nanoparticles (designated as DMMnSiO3 NPs) loaded with indocyanine green (ICG) and natural glucose oxidase (GOD) is established (designated as DIG nanocomposites). As the Mn-O bonds in DMMnSiO3 NPs are susceptive to mildly acidic and reducing environments, the DIG nanocomposites can be rapidly decomposed because of the biodegradation of DMMnSiO3 NPs once internalized into the tumor by the consumption of glutathione (GSH) in TME to weaken the antioxidant capability of the tumors. The released Mn2+ could catalyze endogenous hydrogen peroxide (H2O2) to generate oxygen (O2) to relieve the hypoxia in TME. The generation of O2 may promote the catalyzed oxidation of glucose by GOD, which will cut off nutrient supplies, accompanied by the regeneration of H2O2. The regenerated H2O2 could be sequentially catalyzed by Mn2+ to compensate for the consumed O2, and thus, the catalytic cascade process between Mn2+ and GOD was set up. As a result, a synergistic therapeutic strategy based on T1-weighted magnetic resonance imaging (MRI) of Mn2+, starvation therapy by O2-compensation enhanced catalyzing glucose, dual-model (GSH consumption and O2 compensation) enhanced photodynamic therapy, and effective photothermal therapy of ICG (η = 23.8%) under 808 nm laser irradiation has been successfully established.

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 (Gd3+, Yb3+, and Nd3+) make the nanoplatform possess UCL, MRI, and CT trimode imaging capabilities, thus achieving a multiple imaging modality-guided synergistic therapy.

ZnFe2O4, a semiconductor catalyst with high photocatalytic activity, is ultrasensitive to ultraviolet (UV) light and tumor H2O2 for producing reactive oxygen species (ROS). Thereby, ZnFe2O4 can be used for photodynamic therapy (PDT) from direct electron transfer and the newly defined chemodynamic therapy (CDT) from the Fenton reaction. However, UV light has confined applicability because of its high phototoxicity, low penetration, and speedy attenuation in the biotissue. Herein, an upconversion-mediated nanoplatform with a mesoporous ZnFe2O4 shell was developed for near-infrared (NIR) light enhanced CDT and PDT. The nanoplatform (denoted as Y-UCSZ) was comprised of upconversion nanoparticles (UCNPs), silica shell, and mesoporous ZnFe2O4 shell and was synthesized through a facile hydrothermal method. The UCNPs can efficiently transfer penetrable NIR photons to UV light, which can activate ZnFe2O4 for producing singlet oxygen thus promoting the Fenton reaction for ROS generation. Besides, Y-UCSZ possesses enormous internal space, which is highly beneficial for housing DOX (doxorubicin, a chemotherapeutic agent) to realize chemotherapy. Moreover, the T2-weighted magnetic resonance imaging (MRI) effect from Fe3+ and Gd3+ ions in combination with the inherent upconversion luminescence (UCL) imaging and computed tomography (CT) from the UCNPs makes an all-in-one diagnosis and treatment system. Importantly, in vitro and in vivo assays authenticated excellent biocompatibility of the PEGylated Y-UCSZ (PEG/Y-UCSZ) and high anticancer effectiveness of the DOX loaded PEG/Y-UCSZ (PEG/Y-UCSZ&DOX), indicating its potential application in the cancer treatment field.

Long-term tumor hypoxia has always been a huge obstacle for oxygen dependent photodynamic therapy (PDT) and anticancer drug chemotherapy. Herein, a hollow-structured biophotocatalyst was developed by coating mesoporous cerium oxide (mCeOx) on upconversion nanoparticles (UCNPs, NaGdF4:Yb,Tm@NaGdF4), and it can be initialized with a near-infrared (NIR) laser to achieve PDT with O2 compensation by decomposing the endogenous H2O2 in the tumor microenvironment. A NIR laser with a long wavelength has low phototoxicity to biotissue, and the core–inert shell structured UCNPs can efficiently convert the NIR photons into ultraviolet (UV) light, which can further trigger CeOx to produce reactive oxygen species (ROS). Moreover, the internal space of UCNPs@mCeOx is ideal for storing chemotherapeutic doxorubicin (DOX), and adequate O2 plays a key role in alleviating drug fastness via chemotherapy in hypoxic tumors, thereby strengthening the synergy between PDT and chemotherapy. After being injected into tumor-bearing mice intravenously, the nanomedicine was able to reach the tumor via an enhanced permeability and retention (EPR) effect. In addition, the capability to use the developed nanosystem in computed tomography (CT), magnetic resonance (MR) and upconversion luminescence (UCL) imaging was validated. Significantly, the NIR laser irradiated nanomedicine exhibits an excellent anticancer effect, implying promising theranostic applications.

Gasotransmitters with high therapeutic efficacy and biosafety have been drawing the attention of researchers. Nevertheless, how to effectively deliver gases to and precisely control their generation at the lesion as well as integrate them with other therapies to realize precision therapy have remained elusive. Herein, we report a versatile Cu2+-initiated nitric oxide (NO) nanocomposite for multimodal imaging-guided synergistic chemodynamic/photodynamic/gas therapy. After the nanomedicine was ingested by tumor cells, the acidic tumor microenvironment accelerated the decomposition of CuO2 and simultaneously triggered the Fenton-like catalytic reaction of Cu2+ and H2O2 to produce highly toxic ˙OH. By virtue of the NO generation and glutathione depletion, UMNOCC-PEG can relieve the antioxidant capacity and hypoxia of the tumor to improve the efficiency of chemodynamic therapy (CDT) and photodynamic therapy (PDT). Importantly, NO and reactive oxygen species (ROS) can generate reactive nitrogen species (RNS), which can result in DNA damage, further improving the therapeutic effect (cell apoptosis rate up to 93.4%). Moreover, the inherent properties of lanthanide ions endow UMNOCC-PEG with upconversion luminescence (UCL), CT and MRI trimodal imaging capability, achieving precise cancer treatment. By taking advantage of these features, the strategy developed here may provide a promising application foreground to conquer malignant tumors.

Reactive oxygen species (ROS)-based therapeutic modalities including chemodynamic therapy (CDT) and photodynamic therapy (PDT) hold great promise for conquering malignant tumors. However, these two methods tend to be restricted by the overexpressed glutathione (GSH) and hypoxia in the tumor microenvironment (TME). Here, we develop biodegradable copper/manganese silicate nanosphere (CMSN)-coated lanthanide-doped nanoparticles (LDNPs) for trimodal imaging-guided CDT/PDT synergistic therapy. The tridoped Yb3+/Er3+/Tm3+ in the ultrasmall core and the optimal Yb3+/Ce3+ doping in the shell enable the ultrabright dual-mode upconversion (UC) and downconversion (DC) emissions of LDNPs under near-infrared (NIR) laser excitation. The luminescence in the second near-infrared (NIR-II, 1000-1700 nm) window offers deep-tissue penetration, high spatial resolution, and reduced autofluorescence when used for optical imaging. Significantly, the CMSNs are capable of relieving the hypoxic TME through decomposing H2O2 to produce O2, which can react with the sample to generate 1O2 upon excitation of UC photons (PDT). The GSH-triggered degradation of CMSNs results in the release of Fenton-like Mn2+ and Cu+ ions for •OH generation (CDT); simultaneously, the released Mn2+ ions couple with NIR-II luminescence imaging, computed tomography (CT) imaging, and magnetic resonance (MR) imaging of LDNPs, performing a TME-amplified trimodal effect. In such a nanomedicine, the TME modulation, bimetallic silicate photosensitizer, Fenton-like nanocatalyst, and NIR-II/MR/CT contrast agent were achieved "one for all", thereby realizing highly efficient tumor theranostics.

The therapeutic effect of traditional chemodynamic therapy (CDT) agents is severely restricted by their weakly acidic pH and glutathione (GSH) overexpression in the tumor microenvironment. Here, fusiform-like copper(II)-based tetrakis(4-carboxy phenyl)porphyrin (TCPP) nanoscale metal-organic frameworks (nMOFs) were designed and constructed for the first time (named PCN-224(Cu)-GOD@MnO2). The coated MnO2 layer can not only avoid conjugation of glucose oxidase (GOD) to damage normal cells but also catalyzes the generation of O2 from H2O2 to enhance the oxidation of glucose (Glu) by GOD, which also provides abundant H2O2 for the subsequent Cu+-based Fenton-like reaction. Meanwhile, the Cu2+ chelated to the TCPP ligand is converted to Cu+ by the excess GSH in the tumor, which reduces the tumor antioxidant activity to improve the CDT effect. Next, the Cu+ reacts with the plentiful H2O2 by enzyme catalysis to produce a toxic hydroxyl radical (•OH), and singlet oxygen (1O2) is synchronously generated from combination with Cu+, O2, and H2O via the Russell mechanism. Furthermore, the nanoplatform can be used for both TCPP-based in vivo fluorescence imaging and Mn2+-induced T1-weighted magnetic resonance imaging. In conclusion, fusiform-like PCN-224(Cu)-GOD@MnO2 nMOFs facilitate the therapeutic efficiency of chemodynamic and starvation therapy via combination with relief hypoxia and GSH depletion after acting as an accurate imaging guide.

Inventing a tumor-responsive theranostic nanoconstruct shows great potential for improving the therapeutic outcome on cancer. Herein, a facile in situ growth strategy based on polyoxometalate (POM) integrated with the mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO2) has been developed. The product was named as USP, and can be triggered by 808 nm light for cancer theranostic. The POM is ultra-sensitive to the intratumoral acidity and reducibility, which enables the photothermal conversion of 808 nm photon for photothermal therapy (PTT). The POM endows the nanostructure highly hydrophilic surface, which is very significant for in vivo application. Need to point out, the photothermal conversion ability of POM enhances the inner temperature of doxorubicin (DOX)-loaded USP (USP-DOX), realizing a bioresponsiveness and NIR photon co-enhanced chemo-photothermal therapy. The POM can also obviate the DOX leakage in normal tissues while accelerate DOX release in tumor tissues under NIR irradiation. Significantly, the POM endows the nanomedicine self-assemble property in acidic tumor microenvironment, which is highly beneficial for enhancing intratumoral accumulation. Highly effective anticancer therapy of the developed USP-DOX has been validated by the in vitro and in vivo assays. The Gd3+/Nd3+/Yb3+/Er3+ co-doped UCNPs ensure the nanosystem MRI/CT/UCL imaging functions, thus achieving the integration of therapy and diagnosis.

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 CaO2, we designed and constructed a Ca2+ nanogenerator (named as CaO2-Cu/ICG@PCM) that enables H2O2/O2 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, H2O2, O2 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 H2O2, 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, CaO2-Cu/ICG@PCM could be a promising candidate for bioimaging and tumor therapy.

Photodynamic therapy (PDT) and photothermal therapy (PTT) combined treatment guided by imaging diagnosis has brought the cancer treatment into a new stage. But simple nanoplatforms with multifunctional therapeutic performance are rarely designed. Herein, we adopt ball-milling method to fabricate spherical BiAgOS nanoparticles as photosensitizer to apply for 808 nm near-infrared (NIR) light triggered PDT and PTT co-therapy. The polyethylene glycol (PEG) modified BiAgOS NPs show a great absorption in the range of visible light to near-infrared region. Under 808 nm laser irradiation, BiAgOS-PEG NPs have obvious photothermal and photosensitive effects together with excellent X-ray computed tomography (CT) imaging function. The in vitro and in vivo experiments exhibit that the BiAgOS-PEG NPs have good biocompatibility, excellent tumor cells inhibition effects simultaneously. Our finding described the first use of BiAgOS-PEG NPs as a semiconductor photosensitizer for anti-cancer treatment, providing a promising strategy to fabricate this kind of material for imaging guided NIR light induced combined tumor treatment.

Multimodal synergistic therapy based on photodynamic therapy (PDT), photothermal therapy (PTT), and chemodynamic therapy (CDT) has attracted increasing attention in cancer therapy. However, the scant therapeutic efficiency is always a barrier for further application. Herein, a smart tumor microenvironment (TME) responsive nanocatalysts are developed by adopting Fe-Mn layered double hydroxides (FeMn-LDH) as an effective photothermal nanocarrier to load mesoporous silica and chlorin e6 (Ce6)-covalently coated upconversion nanoparticles (UCSP) for multimodal imaging for directed therapy. Under acidic TME, FeMn-LDH degrades into Fe3+ and Mn2+ ions to initiate a Fenton-like reaction inducing CDT and enhancing magnetic resonance imaging. Additionally, Fe3+ can decompose H2 O2 to oxygen (O2 ), enhancing PDT guided by UCSP. As a representative noninvasive imaging probe, the upconversion luminescence will recover after decomposition of FeMn-LDH, and provide high-resolution upconversion luminescent imaging guidance for pinpointed PDT. Moreover, the photothermal properties of FeMn-LDH can further enhance CDT effects. The synergistic therapy and multifunctional imaging can realize the integration of diagnosis and treatment.

Nanocatalytic therapy, using artificial nanoscale enzyme mimics (nanozymes), is an emerging technology for therapeutic treatment of various malignant tumors. However, the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME) restrains their biomedical applications. Here, a versatile and bacteria-like PEG/Ce-Bi@DMSN nanozyme is developed by coating uniform Bi2 S3 nanorods (NRs) with dendritic mesoporous silica (Bi2 S3 @DMSN) and then decorating ultrasmall ceria nanozymes into the large mesopores of Bi2 S3 @DMSN. The nanozymes exhibit dual enzyme-mimic catalytic activities (peroxidase-mimic and catalase-mimic) under acidic conditions that can regulate the TME, that is, simultaneously elevate oxidative stress and relieve hypoxia. In addition, the nanozymes can effectively consume the overexpressed glutathione (GSH) through redox reaction. Photothermal therapy (PTT) is introduced to synergistically improve the dual enzyme-mimicking catalytic activities and depletion of the overexpressed GSH in the tumors by photonic hyperthermia. This is achieved by taking advantage of the desirable light absorbance in the second near-infrared (NIR-II) window of the PEG/Ce-Bi@DMSN nanozymes. Subsequently the reactive oxygen species (ROS)-mediated therapeutic efficiency is significantly improved. Therefore, this study provides a proof of concept of hyperthermia-augmented multi-enzymatic activities of nanozymes for tumor ablation.

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.