Nanoghosts: Harnessing Mesenchymal Stem Cell Membrane for Construction of Drug Delivery Platforms Via Optimized Biomimetics.

Mesenchymal stem cells (MSCs) are becoming hotspots for application in disease therapies recently, combining with biomaterials and drug delivery system. A major advantage of MSCs applied in drug delivery system is that these cells enable specific targeting and releasing of cargos to the disease sites. However, the potential tumor tropic effects of MSCs raised concerns on biosafety. To solve this problem, there are emerging methods of isolating cell membranes and developing nanoformulations to perform drug delivery, which avoids concerns on biosafety without disturbing the membrane functions of specific polarizing and locating. These cargoes are so called "nanoghosts." This review article summarizes the current applications of nanoghosts, the promising potential of MSCs to be applied in membrane isolation and nanoghost construction, and possible approaches to develop better drug delivery system harnessing from MSC ghost cell membranes.

An Ultrasound-Triggered STING Pathway Nanoagonist for Enhanced Chemotherapy-Induced Immunogenic Cell Death.

Although chemotherapy has the potential to induce tumor immunotherapy via immunogenic cell death (ICD) effects, how to control the intensity of the immune responses still deserves further exploration. Herein, a controllable ultrasound (US)-triggered chemo-immunotherapy nanoagonist is successfully synthesized by utilizing the pH and reactive oxygen species (ROS) dual-responsive PEG-polyphenol to assemble sonosensitizer zinc oxide (ZnO) and doxorubicin (DOX). The PZnO@DOX nanoparticles have an intelligent disassembly to release DOX and zinc ions in acidic pH conditions. Notably, US irradiation generates ROS by sonodynamic therapy and accelerates the drug release process. Interestingly, after the PZnO@DOX+US treatment, the injured cells release double-stranded DNA (dsDNA) from the nucleus and mitochondria into the cytosol. Subsequently, both the dsDNA and zinc ions bind with cyclic GMP-AMP synthase and activate the stimulator of interferon genes (STING) pathway, resulting in the dendritic cell maturation, ultimately promoting DOX-induced ICD effects and antigen-specific T cell immunity. Therefore, chemotherapy-induced immune responses can be modulated by non-invasive control of US.

Kilogram scale facile synthesis and systematic characterization of a Gd-macrochelate as T1-weighted magnetic resonance imaging contrast agent.

To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the coordination of Gd3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r2/r1 ratio of the reported Gd macrochelates that is an important factor for T1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r1 value of 16.35 mM-1 s-1 and r2/r1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 â„ƒ or 1.8 cP at 37 â„ƒ, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications.

Metal-Phenolic Nanomaterial with Organelle-Level Precision Primes Antitumor Immunity via mtDNA-dependent cGAS-STING Activation.

New generation of nanomaterials with organelle-level precision provide significant promise for targeted attacks on mitochondria, exhibiting remarkable therapeutic potency. Here, we report a novel amphiphilic phenolic polymer (PF) for the mitochondria-targeted photodynamic therapy (PDT), which can trigger excessive mitochondrial DNA (mtDNA) damages by the synergistic action of oxidative stress and furan-mediated DNA cross-linking. Moreover, the phenolic units on PF enable further self-assembly with Mn2+ via metal-phenolic coordination to form metal-phenolic nanomaterial (PFM). We focus on the synergistic activation of the cGAS-STING pathway by Mn2+ and tumor-derived mtDNA in tumor-associated macrophages (TAMs), and subsequently repolarizing M2-like TAMs to M1 phenotype. We highlight that PFM facilitates the cGAS-STING-dependent immunity at the organelle level for potent antitumor efficacy.

Phototheranostic Metal-Phenolic Networks with Antiexosomal PD-L1 Enhanced Ferroptosis for Synergistic Immunotherapy.

Tumor-derived exosome can suppress dendritic cells (DCs) and T cells functions. Excessive secretion of exosomal programmed death-ligand 1 (PD-L1) results in therapeutic resistance to PD-1/PD-L1 immunotherapy and clinical failure. Restored T cells by antiexosomal PD-L1 tactic can intensify ferroptosis of tumor cells and vice versa. Diminishing exosomal suppression and establishing a nexus of antiexosomal PD-L1 and ferroptosis may rescue the discouraging antitumor immunity. Here, we engineered phototheranostic metal-phenolic networks (PFG MPNs) by an assembly of semiconductor polymers encapsulating ferroptosis inducer (Fe3+) and exosome inhibitor (GW4869). The PFG MPNs elicited superior near-infrared II fluorescence/photoacoustic imaging tracking performance for a precise photothermal therapy (PTT). PTT-augmented immunogenic cell death relieved exosomal silencing on DC maturation. GW4869 mediated PD-L1 based exosomal inhibition revitalized T cells and enhanced the ferroptosis. This novel synergy of PTT with antiexosomal PD-L1 enhanced ferroptosis evoked potent antitumor immunity in B16F10 tumors and immunological memory against metastatic tumors in lymph nodes.

A Metal-Phenolic Nanosensitizer Performs Hydrogen Sulfide-Reprogrammed Oxygen Metabolism for Cancer Radiotherapy Intensification and Immunogenicity.

Radiotherapy (RT) is hampered by the limited oxygen in tumors, which could be potentiated via reprogramming the oxygen metabolism and increasing the oxygen utilization efficiency. Herein, a metal-phenolic nanosensitizer (Hf-PSP-DTC@PLX) was integrated via an acid-sensitive hydrogen sulfide (H2 S) donor (polyethylene glycol-co-polydithiocarbamates, PEG-DTC) and a hafnium-chelated polyphenolic semiconducting polymer (Hf-PSP) in an amphiphilic polymer (poloxamer F127, PLX). Hf-PSP-DTC@PLX elicited a high imaging performance for precise RT and generated H2 S to reduce the cellular oxygen consumption rate via mitochondrial respiration inhibition, which reprogrammed the oxygen metabolism for improvement of the tumor oxygenation. Then, Hf-sensitization could fully utilize the well-preserved oxygen to intensify RT efficacy and activate immunogenicity. Such a synergistic strategy for improvement of oxygenation and oxygen utilization would have great potential in optimizing oxygen-dependent therapeutics.

Recent Advances in Metal-Phenolic Networks for Cancer Theranostics.

Nanomedicine integrates different functional materials to realize the customization of carriers, aiming at increasing the cancer therapeutic efficacy and reducing the off-target toxicity. However, efforts on developing new drug carriers that combine precise diagnosis and accurate treatment have met challenges of uneasy synthesis, poor stability, difficult metabolism, and high cytotoxicity. Metal-phenolic networks (MPNs), making use of the coordination between phenolic ligands and metal ions, have emerged as promising candidates for nanomedicine, most notably through the service as multifunctional theranostic nanoplatforms. MPNs present unique properties, such as rapid preparation, negligible cytotoxicity, and pH responsiveness. Additionally, MPNs can be further modified and functionalized to meet specific application requirements. Here, the classification of polyphenols is first summarized, followed by the introduction of the properties and preparation strategies of MPNs. Then, their recent advances in biomedical sciences including bioimaging and anti-tumor therapies are highlighted. Finally, the main limitations, challenges, and outlooks regarding MPNs are raised and discussed.

Remodeling of Tumor Microenvironment by Tumor-Targeting Nanozymes Enhances Immune Activation of CAR T Cells for Combination Therapy.

Targeting B7-H3 chimeric antigen receptor (CAR) T cells has antitumor potential for therapy of non-small cell lung cancer (NSCLC) in preclinical studies. However, CAR T cell therapy remains a formidable challenge for the treatment of solid tumors due to the heterogeneous and immunosuppressive tumor microenvironment (TME). Nanozymes exhibit merits modulating the immunosuppression of the tumor milieu. Here, a synergetic strategy by combination of nanozymes and CAR T cells in solid tumors is described. This nanozyme with dual photothermal-nanocatalytic properties is endowed to remodel TME by destroying its compact structure. It is found that the B7-H3 CAR T cells infused in mice engrafted with the NSCLC cells have superior antitumor activity after nanozyme ablation of the tumor. Importantly, it is found that the changes altered immune-hostile cancer environment, resulting in enhanced activation and infiltration of B7-H3 CAR T cells. The first evidence that the process of combination nanozyme therapy effectively improves the therapeutic index of CAR T cells is presented. Thus, this study clearly supports that the TME-immunomodulated nanozyme is a promising tool to improve the therapeutic obstacles of CAR T cells against solid tumors.

Donut-like MOFs of copper/nicotinic acid and composite hydrogels with superior bioactivity for rh-bFGF delivering and skin wound healing.

BACKGROUND: Skin injury and the resultant defects are common clinical problems, and usually lead to chronic skin ulcers and even life-threatening diseases. Copper, an essential trace element of human body, has been reported to promote the regeneration of skin by stimulating proliferation of endothelial cell and enhance angiogenesis. RESULTS: Herein, we have prepared a new donut-like metal-organic frameworks (MOF) of copper-nicotinic acid (CuNA) by a simple solvothermal reaction. The rough surface of CuNA is beneficial for loading/release basic fibroblast growth factor (bFGF). The CuNAs with/without bFGF are easily processed into a light-responsive composite hydrogel with GelMA, which not only show excellent mechanical properties, but also display superior biocompatibility, antibacterial ability and bioactivity. Moreover, in the in vivo full-thickness defect model of skin wound, the resultant CuNA-bFGF@GelMA hydrogels significantly accelerate the wound healing, by simultaneously inhibiting the inflammatory response, promoting the new blood vessels formation and the deposition of collagen and elastic fibers. CONCLUSIONS: Considering the superior biocompatibility, antibacterial ability and bioactivity, the CuNA and its composite light-responsive hydrogel system will be promising in the applications of skin and even other tissue regeneration.

Polyphenol-Based Nanomedicine Evokes Immune Activation for Combination Cancer Treatment.

Engineering multifunctional nanoplatforms with high therapeutic benefits has become a promising strategy for intractable cancer treatment. A novel polyphenol-based nanocomplex was designed to evoke highly efficacious cancer immunosurveillance while localizing therapy on the primary tumor and to minimize systemic side effects. This nanocomplex is prepared via metal-polyphenol coordination by encapsulating a natural polyphenol, gossypol, and a newly synthesized polyphenol derivative, polyethylene glycol-Chlorin e6 (Ce6). The combination of gossypol from cotton and the photosensitizer Ce6 can induce chemotherapeutic/photodynamic immunogenic cancer cell death upon laser irradiation, which is supported by a rich maturation of dendritic cells, concentrated secretion of inflammatory cytokines, and significant inhibition of distant untreated tumors. Finally, an assistance of the programmed-cell-death ligand-1 checkpoint-blockade immunotherapy can enhance the anti-tumor immune stimulation of our nanoplatform to a higher level.

Efficient Polysulfide-Based Nanotheranostics for Triple-Negative Breast Cancer: Ratiometric Photoacoustics Monitored Tumor Microenvironment-Initiated H2 S Therapy.

The incidence of triple-negative breast cancer (TNBC) is difficult to predict, and TNBC has a high mortality rate among women worldwide. In this study, a theranostics approach is developed for TNBC with ratiometric photoacoustic monitored thiol-initiated hydrogen sulfide (H2 S) therapy. The ratiometric photoacoustic (PA) probe (CY) with a thiol-initiated H2 S donor (PSD) to form a nanosystem (CY-PSD nanoparticles) is integrated. In this theranostics approach, H2 S generated from PSD is sensed by CY based on ratiometric PA signals, which simultaneously pinpoints the tumor region. Additionally, H2 S is cytotoxic toward TNBC cells (MDA-MB 231), showing a tumor inhibition rate of 63%. To further verify its pharmacological mechanism, proteomics analysis is performed on tumors treated with CY-PSD nanoparticles. Cells are killed by the significant mitochondrial dysfunction via supressed energy supply and apoptosis initiation. Besides, the observed inhibition of oxidative stress also generates the cytotoxicity. Significant Kyoto Encyclopedia of Genes Genomes pathways related to TNBC are found to be inhibited. This H2 S theranostics approach updates the current anticancer therapies which brings promise for women suffering malignant breast cancer.

NIR II-Excited and pH-Responsive Ultrasmall Nanoplatform for Deep Optical Tissue and Drug Delivery Penetration and Effective Cancer Chemophototherapy.

The limited tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall drug delivery nanoplatform was fabricated based on BSA-stabilized CuS nanoparticles (BSA@CuS NPs). The BSA@CuS NPs effectively encapsulated doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@CuS@DOX NPs). The BSA@CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in tumor sites, induced tumor hyperthermia, and generated remarkably high ROS levels in tumor sites upon NIR-II laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of chemotherapy and phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep tumor penetration as an effective antitumor therapy.

Dual Role of Doxorubicin for Photopolymerization and Therapy.

In this study, we report dual roles for doxorubicin (DOX), which can serve as an antitumor drug as well as a cocatalyst for a photoliving radical polymerization. DOX enhances the polymerization rates of a broad range of monomers, including acrylamide, acrylate, and methacrylates, allowing for high monomer conversion and well-defined molecular weights under irradiation with a blue light-emitting diode light (λmax = 485 nm, 2.2 mW/cm2). Utilizing this property, the photopolymerization of N,N-diethylacrylamide was performed in the presence of a poly(oligo(ethylene glycol) methyl ether acrylate) macroreversible addition-fragmentation chain transfer (macroRAFT) agent to prepare polymeric nanoparticles via aqueous polymerization-induced self-assembly (PISA). By varying the monomer:macroRAFT ratio, spherical polymeric nanoparticles of various diameters could be produced. Most notably, DOX was successfully encapsulated into the hydrophobic core of nanoparticles during the PISA process. The DOX-loaded nanoparticles were effectively uptaken into tumor cells and significantly inhibited the proliferation of tumor cells, demonstrating that the DOX bioactivity was not affected by the polymerization reaction.

Recent advances in nanomaterial-based synergistic combination cancer immunotherapy.

In recent years, conventional treatments including surgery, chemotherapy and radiotherapy have been the main approaches in tumour therapy. Cancer immunotherapy is a new therapeutic modality to fight cancer by harnessing the power of patients' own immune system. Ongoing research related to these therapies has demonstrated their advantages and intrinsic limitations. Nanomaterial-based platforms are utilized in these emerging fields. In particular, a combination of other treatment methods with cancer immunotherapy to achieve precision medicine and prevent recurrence and metastasis, could improve patients' outcome. The combined multiple treatments have superior efficacy to any monotherapy alone in producing improved anti-cancer activity. Therefore, it's necessary to summarise research advances in nanomaterial-based combination cancer immunotherapy contributing to clinical transformation. This review is based on the principles of cancer immunotherapy and the combined treatment design reflected by advances in materials science, including the structures of nanoplatforms and their underlying mechanisms towards cancer. The ultimate goals are to stimulate the design of better strategies for versatile use in the future based on biomaterial engineering methods to enhance the efficacy of combined cancer treatments, and to provide new ideas for the prospects of a synergistic cancer combination immunotherapy for clinical application transformation.

Hybrid Nanomedicine Fabricated from Photosensitizer-Terminated Metal-Organic Framework Nanoparticles for Photodynamic Therapy and Hypoxia-Activated Cascade Chemotherapy.

During photodynamic therapy (PDT), severe hypoxia often occurs as an undesirable limitation of PDT owing to the O2 -consuming photodynamic process, compromising the effectiveness of PDT. To overcome this problem, several strategies aiming to improve tumor oxygenation are developed. Unlike these traditional approaches, an opposite method combining hypoxia-activated prodrug and PDT may provide a promising strategy for cancer synergistic therapy. In light of this, azido-/photosensitizer-terminated UiO-66 nanoscale metal-organic frameworks (UiO-66-H/N3 NMOFs) which serve as nanocarriers for the bioreductive prodrug banoxantrone (AQ4N) are engineered. Owing to the effective shielding of the nanoparticles, the stability of AQ4N is well preserved, highlighting the vital function of the nanocarriers. By virtue of strain-promoted azide-alkyne cycloaddition, the nanocarriers are further decorated with a dense PEG layer to enhance their dispersion in the physiological environment and improve their therapeutic performance. Both in vitro and in vivo studies reveal that the O2 -depleting PDT process indeed aggravates intracellular/tumor hypoxia that activates the cytotoxicity of AQ4N through a cascade process, consequently achieving PDT-induced and hypoxia-activated synergistic therapy. Benefiting from the localized therapeutic effect of PDT and hypoxia-activated cytotoxicity of AQ4N, this hybrid nanomedicine exhibits enhanced therapeutic efficacy with negligible systemic toxicity, making it a promising candidate for cancer therapy.

An Albumin Sandwich Enhances in Vivo Circulation and Stability of Metabolically Labile Peptides.

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.

Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake.

Drug carriers typically require both stealth and targeting properties to minimize nonspecific interactions with healthy cells and increase specific interaction with diseased cells. Herein, the assembly of targeted poly(ethylene glycol) (PEG) particles functionalized with cyclic peptides containing Arg-Gly-Asp (RGD) (ligand) using a mesoporous silica templating method is reported. The influence of PEG molecular weight, ligand-to-PEG molecule ratio, and particle size on cancer cell targeting to balance stealth and targeting of the engineered PEG particles is investigated. RGD-functionalized PEG particles (PEG-RGD particles) efficiently target U-87 MG cancer cells under static and flow conditions in vitro, whereas PEG and cyclic peptides containing Arg-Asp-Gly (RDG)-functionalized PEG (PEG-RDG) particles display negligible interaction with the same cells. Increasing the ligand-to-PEG molecule ratio improves cell targeting. In addition, the targeted PEG-RGD particles improve cell uptake via receptor-mediated endocytosis, which is desirable for intracellular drug delivery. The PEG-RGD particles show improved tumor targeting (14% ID g-1) when compared with the PEG (3% ID g-1) and PEG-RDG (7% ID g-1) particles in vivo, although the PEG-RGD particles show comparatively higher spleen and liver accumulation. The targeted PEG particles represent a platform for developing particles aimed at balancing nonspecific and specific interactions in biological systems.

A Catalase-Like Metal-Organic Framework Nanohybrid for O2 -Evolving Synergistic Chemoradiotherapy.

Tumor hypoxia, the "Achilles' heel" of current cancer therapies, is indispensable to drug resistance and poor therapeutic outcomes especially for radiotherapy. Here we propose an in situ catalytic oxygenation strategy in tumor using porphyrinic metal-organic framework (MOF)-gold nanoparticles (AuNPs) nanohybrid as a therapeutic platform to achieve O2 -evolving chemoradiotherapy. The AuNPs decorated on the surface of MOF effectively stabilize the nanocomposite and serve as radiosensitizers, whereas the MOF scaffold acts as a container to encapsulate chemotherapeutic drug doxorubicin. In vitro and in vivo studies verify that the catalase-like nanohybrid significantly enhances the radiotherapy effect, alleviating tumor hypoxia and achieving synergistic anticancer efficacy. This hybrid nanomaterial remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theranostic nanomedicines.

Glutathione Mediated Size-Tunable UCNPs-Pt(IV)-ZnFe2 O4 Nanocomposite for Multiple Bioimaging Guided Synergetic Therapy.

Here a multifunctional nanoplatform (upconversion nanoparticles (UCNPs)-platinum(IV) (Pt(IV))-ZnFe2 O4 , denoted as UCPZ) is designed for collaborative cancer treatment, including photodynamic therapy (PDT), chemotherapy, and Fenton reaction. In the system, the UCNPs triggered by near-infrared light can convert low energy photons to high energy ones, which act as the UV-vis source to simultaneously mediate the PDT effect and Fenton's reaction of ZnFe2 O4 nanoparticles. Meanwhile, the Pt(IV) prodrugs can be reduced to high virulent Pt(II) by glutathione in the cancer cells, which can bond to DNA and inhibit the copy of DNA. The synergistic therapeutic effect is verified in vitro and in vivo results. The cleavage of Pt(IV) from UCNPs during the reduction process can shift the larger UCPZ nanoparticles (NPs) to the smaller ones, which promotes the enhanced permeability and retention (EPR) and deep tumor penetration. In addition, due to the inherent upconversion luminescence (UCL) and the doped Yb3+ and Fe3+ in UCPZ, this system can serve as a multimodality bioimaging contrast agent, covering UCL, X-ray computed tomography, magnetic resonance imaging, and photoacoustic. A smart all-in-one imaging-guided diagnosis and treatment system is realized, which should have a potential value in the treatment of tumor.

Quad-Model Imaging-Guided High-Efficiency Phototherapy Based on Upconversion Nanoparticles and ZnFe2O4 Integrated Graphene Oxide.

The strategy of diagnosis-to-therapy to realize the integration of imaging and high antitumor efficiency has become the most promising method. Light-induced therapeutic technologies have drawn considerable interest. However, the limited penetration depth of UV/vis excitation and relatively low efficiency are the main obstacles for its further clinic application. For this concern, we presented a facile method to anchor ultrasmall ZnFe2O4 nanoparticles and upconversion luminescence nanoparticles (UCNPs) on graphene oxide (GO) nanosheets (GO/ZnFe2O4/UCNPs, abbreviated as GZUC). To solve the penetration question, here we introduced Tm3+-doped UCNPs to convert the high-penetrated near-infrared (NIR) light into UV/vis photons to activate the photodynamic process. In this system, the dual phototherapy from GO and ZnFe2O4 has been realized upon NIR laser irradiation. Combined with the photodynamic therapy (PDT) based on Fenton reaction that ZnFe2O4 nanoparticles react with excessive H2O2 in tumor microenvironment to produce toxic hydroxyl radicals (·OH), an excellent anticancer efficiency has been achieved. Furthermore, 4-fold imaging including upconversion luminescence (UCL), computed tomography (CT), magnetic resonance imaging (MRI) and photoacoustic tomography (PAT) has been obtained due to its intrinsic properties, thereby successfully realizing diagnosis-monitored therapy. Our demonstration provided a feasible strategy to solve the main problems in current light-triggered theranostic.