Smart Tumor Microenvironment‐Responsive Nanotheranostic Agent for Effective Cancer Therapy

The tumor microenvironment (TME), which includes acidic and hypoxic conditions, severely impedes the therapeutic efficacy of antitumor agents. Herein, MnO₂‐loaded, bovine serum albumin, and PEG co‐modified mesoporous CaSiO₃ nanoparticles (CaM‐PB NPs) are developed as a nanoplatform with sequential theranostic functions for the engineering of TME. The MnO₂ NPs generate O₂ in situ by reacting with endogenous H₂O₂, relieving the hypoxic state of the TME that further modulates the cancer cell cycle status to S phase, which improves the potency of co‐loaded S phase‐sensitive chemotherapeutic drugs. After the hypoxia relief, CaM‐PB can sustainably release drugs due to the enlarged pores of mesoporous CaSiO₃ in the acidic TME, preventing the drug pre‐leakage into the blood circulation and insufficient drug accumulation at tumor sites. Moreover, the Mn²⁺ released from the MnO₂ NPs at tumor sites can potentially serve as a diagnostic agent, enabling the identification of tumor regions by T₁‐weighted magnetic resonance imaging during therapy. In vivo pharmacodynamics results demonstrate that these synergetic effects caused by CaM‐PB NPs significantly contribute to the inhibition of tumor progression. Therefore, the CaM‐PB NPs with sequential theranostic functions are a promising system for effective cancer therapy.     

Targeted Tumor Hypoxia Dual‐Mode CT/MR Imaging and Enhanced Radiation Therapy Using Dendrimer‐Based Nanosensitizers

The efficacy of radiation therapy (RT) is often limited by the poor response of hypoxia inside most solid tumors. The development of a theranostic nanoplatform for precision‐imaging‐guided sensitized RT for tumor hypoxia is still challenging. Herein, the creation of hypoxia‐targeted dendrimer‐entrapped gold nanoparticles complexed with gadolinium(III) (Gd‐Au DENPs‐Nit) for dual‐mode CT/MR imaging and sensitized RT of hypoxic tumors is reported. In this work, generation 5 poly(amidoamine) dendrimers are partially conjugated with Gd(III) chelator, entrapped with Au nanoparticles, and conjugated with hypoxia‐targeting agent nitroimidazole via a polyethylene glycol linker, and ending with chelation of Gd(III) and conversion of their leftover amine termini to acetamides. The designed dendrimer‐based nanohybrids with 3.2 nm Au cores exhibit an excellent X‐ray attenuation effect, acceptable r₁ relaxivity (1.32 mM^?1 s^?1), and enhanced cellular uptake in hypoxic cancer cells, affording efficient dual‐mode CT/MR imaging of tumor hypoxia. Under X‐ray irradiation, the Gd‐Au DENPs‐Nit nanohybrids can produce reactive oxygen species, promote DNA damage, and prevent DNA repair, facilitating sensitized RT of hypoxic cancer cells in vitro and tumor hypoxia in vivo. The developed hypoxia‐targeted dendrimer‐based nanohybrids may be employed as both contrast agents and nanosensitizers for precision tumor hypoxia imaging and sensitized tumor RT.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Copper(I) Phosphide Nanocrystals for In Situ Self‐Generation Magnetic Resonance Imaging‐Guided Photothermal‐Enhanced Chemodynamic Synergetic Therapy Resisting Deep‐Seated Tumor

Fe‐based Fenton agents can generate highly reactive and toxic hydroxyl radicals (·OH) in the tumor microenvironment (TME) for chemodynamic therapy (CDT) with high specificity. However, the strict condition (lower pH environment: 3–4) of the highly efficient Fenton reaction limits its practical application in the clinic. Development of new CDT agents more suitable for TME is significant and challenging. A highly efficient Cu(I)‐based CDT agent, copper(I) phosphide nanocrystals (CP NCs), which is more adaptable to the pH value of TME than Fe‐based agents, thereby producing more ·OH to trigger the apoptosis of cancer cells, is prepared. Moreover, the excess glutathione (GSH) in TME can reduce the Cu(II) produced by a Fenton‐like reaction to Cu(I), further increasing the generation rate of ·OH and relieving tumor antioxidant ability. Furthermore, owing to their strong absorption in the NIR II region, CP NCs exhibit an excellent photothermal conversion effect, which can further improve the Fenton reaction. What is more, CP NCs can act as in situ self‐generation magnetic resonance imaging (MRI) agents owing to the generation of paramagnetic Cu(II) in response to excess H₂O₂ in the TME. These properties may open up the exploration of copper‐based materials in clinical application of self‐generation imaging‐guided synergetic treatment.     

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe₂O₃ magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l ‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l ‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l ‐TRAIL@MMBs. Such RGD‐l ‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l ‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l ‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.     

An O2 Self‐Supplementing and Reactive‐Oxygen‐Species‐Circulating Amplified Nanoplatform via H2O/H2O2 Splitting for Tumor Imaging and Photodynamic Therapy

Conventional photodynamic therapy (PDT) has limited applications in clinical cancer therapy due to the insufficient O₂ supply, inefficient reactive oxygen species (ROS) generation, and low penetration depth of light. In this work, a multifunctional nanoplatform, upconversion nanoparticles (UCNPs)@TiO₂@MnO₂ core/shell/sheet nanocomposites (UTMs), is designed and constructed to overcome these drawbacks by generating O₂ in situ, amplifying the content of singlet oxygen (¹O₂) and hydroxyl radical (?OH) via water‐splitting, and utilizing 980 nm near‐infrared (NIR) light to increase penetration depth. Once UTMs are accumulated at tumor site, intracellular H₂O₂ is catalyzed by MnO₂ nanosheets to generate O₂ for improving oxygen‐dependent PDT. Simultaneously, with the decomposition of MnO₂ nanosheets and 980 nm NIR irradiation, UCNPs can efficiently convert NIR to ultraviolet light to activate TiO₂ and generate toxic ROS for deep tumor therapy. In addition, UCNPs and decomposed Mn²⁺ can be used for further upconversion luminescence and magnetic resonance imaging in tumor site. Both in vitro and in vivo experiments demonstrate that this nanoplatform can significantly improve PDT efficiency with tumor imaging capability, which will find great potential in the fight against tumor.     

Persistent Regulation of Tumor Microenvironment via Circulating Catalysis of MnFe2O4@Metal–Organic Frameworks for Enhanced Photodynamic Therapy

Reactive oxygen species (ROS)‐based cancer therapy, such as photodynamic therapy (PDT), is subject to the hypoxia and overexpressed glutathione (GSH) found in the tumor microenvironment (TME). Herein, a novel strategy is reported to continuously and simultaneously regulate tumor hypoxia and reducibility in order to achieve the desired therapeutic effect. To accomplish this, a biocompatible nanoplatform (MnFe₂O₄@metal–organic framework (MOF)) is developed by integrating a coating of porphyrin‐based MOF as the photosensitizer and manganese ferrite nanoparticle (MnFe₂O₄) as the nanoenzyme. The synthetic MnFe₂O₄@MOF nanoplatform exhibits both catalase‐like and glutathione peroxidase‐like activities. Once internalized in the tumor, the nanoplatform can continuously catalyze H₂O₂ to produce O₂ to overcome the tumor hypoxia by cyclic Fenton reaction. Meanwhile, combined with the Fenton reaction, MnFe₂O₄@MOF is able to persistently consume GSH in the presence of H₂O₂, which decreases the depletion of ROS upon laser irradiation during PDT and achieves better therapeutic efficacy in vitro and in vivo. Moreover, the nanoplatform integrates a treatment modality with magnetic resonance imaging, along with persistent regulation of TME, to promote more precise and effective treatment for future clinical application.     

Mesoporous Polydopamine Carrying Manganese Carbonyl Responds to Tumor Microenvironment for Multimodal Imaging‐Guided Cancer Therapy

Multifunctional nanodrugs integrating multiple therapeutic and imaging functions may find tremendous biomedical applications. However, the development of a simple yet potent theranostic nanosystem with a high payload and microenvironment responsiveness enhancing imaging‐guided cancer therapy is still a great challenge. Herein, a kind of MnCO‐entrapped mesoporous polydopamine nanoparticles are developed, which reach a 1.5 mg payload per gram carrier and exhibit marked theranostic capability through effective CO/Mn²⁺ generation and photothermal conversion inside the H⁺ and H₂O₂‐enriched tumor microenvironment, for a magnetic resonance/photoacoustic bimodal imaging‐guided tumor therapy. The multifunctional nanosystem exhibits a biocompatibility highly desirable for in vivo application and superior performance in inhibiting tumor growth and recurrence via combination CO and photothermal therapy.     

Metal–Organic Framework Assisted and Tumor Microenvironment Modulated Synergistic Image‐Guided Photo‐Chemo Therapy

The complex tumor microenvironment (TME) and nonspecific drug targeting limit the clinical efficacy of photodynamic therapy in combination with chemotherapy. Herein, a metal–organic framework (MOF) assisted strategy is reported that modulates TME by reducing tumor hypoxia and intracellular glutathione (GSH) and offers targeted delivery and controlled release of the trapped chemodrug. Platinum(IV)‐diazido complex (Pt(IV)) is loaded inside a Cu(II) carboxylate‐based MOF, MOF‐199, and an aggregation‐induced‐emission photosensitizer, TBD, is conjugated to polyethylene glycol for encapsulating Pt(IV)‐loaded MOF‐199. Once the fabricated TBD‐Pt(IV)@MOF‐199 nanoparticles are internalized by cancer cells, MOF‐199 consumes intracellular GSH and decomposes to fragments to release Pt(IV). Upon light irradiation, the released Pt(IV) generates O₂ that relieves hypoxia and produces Pt(II)‐based chemodrug inside cancer cells. Concomitantly, efficient reactive oxygen species generation and bright emission are afforded by TBD, resulting in synergistic image‐guided photo‐chemo therapy with enhanced efficacies and mitigated side effects.     

Enhanced Nanodrug Delivery to Solid Tumors Based on a Tumor Vasculature‐Targeted Strategy

Tumor angiogenesis is a hallmark of tumor growth and metastasis, and inhibition of tumor angiogenesis is an effective strategy for tumor therapy. The high expression levels of specific biomarkers such as integrin receptors (e.g., α_vβ₃) in the endothelium of tumor vessels make angiogenesis an ideal target for drug delivery and thus tumor therapy. Herein, a new nanodrug (T&D@RGD‐Ag₂S) is presented, which can effectively inhibit tumor growth by integrating the specific recognition peptide cyclo(Arg‐Gly‐Asp‐d‐Phe‐Cys) (cRGD) for tumor vascular targeting, the broad‐spectrum endothelial inhibitor O‐(chloroacetyl‐carbamoyl) fumagillol (TNP‐470), and chemotherapeutic drug doxorubicin (DOX) for synergetic tumor therapy. The results show that the T&D@RGD‐Ag₂S nanodrug rapidly and specifically binds to the tumor vasculature after intravenous injection. Tumor vascular density is greatly reduced following effective angiogenesis inhibition by TNP‐470. Meanwhile, increased delivery of DOX deep into the tumor induces extensive tumor apoptosis, resulting in remarkable tumor growth inhibition in a human U87‐MG malignant glioma xenograft model. In addition, the therapeutic effects of T&D@RGD‐Ag₂S on inhibiting tumor growth and decreasing vessel density are monitored in situ using near‐infrared II (NIR‐II) fluorescence imaging of Ag₂S quantum dots. This tumor vasculature‐targeted strategy can be extended as a general method for treating a broad range of tumors and holds promise for future clinical applications.     

A Novel Theranostic Nanoplatform Based on Pd@Pt‐PEG‐Ce6 for Enhanced Photodynamic Therapy by Modulating Tumor Hypoxia Microenvironment

Photodynamic therapy (PDT), which utilizes reactive oxygen species to kill cancer cells, has found wide applications in cancer treatment. However, the hypoxic nature of most solid tumors can severely restrict the efficiency of PDT. Meanwhile, the hydrophobicity and limited tumor selectivity of some photosensitizers also reduce their PDT efficacy. Herein, a photosensitizer‐Pd@Pt nanosystem (Pd@Pt‐PEG‐Ce6) is designed for highly efficient PDT by overcoming these limitations. In the nanofabrication, Pd@Pt nanoplates, exhibiting catalase‐like activity to decompose H₂O₂ to generate oxygen, are first modified with bifunctional PEG (SH‐PEG‐NH₂). Then the Pd@Pt‐PEG is further covalently conjugated with the photosensitizer chlorin e6 (Ce6) to get Pd@Pt‐PEG‐Ce6 nanocomposite. The Pd@Pt‐PEG‐Ce6 exhibits good biocompatibility, long blood circulation half‐life, efficient tumor accumulation, and outstanding imaging properties. Both in vitro and in vivo experimental results clearly indicate that Pd@Pt‐PEG‐Ce6 effectively delivers photosensitizers to cancer cells/tumor sites and triggers the decomposition of endogenous H₂O₂ to produce oxygen, resulting in a remarkably enhanced PDT efficacy. Moreover, the moderate photothermal effect of Pd@Pt nanoplates also strengthen the PDT of Pd@Pt‐PEG‐Ce6. Therefore, by integrating the merits of high tumor‐specific accumulation, hypoxia modulation function, and mild photothermal effect into a single nanoagent, Pd@Pt‐PEG‐Ce6 readily acts as an ideal nanotherapeutic platform for enhanced cancer PDT.     

Magnetite Nanostructured Porous Hollow Helical Microswimmers for Targeted Delivery

Bacteria‐inspired magnetic helical micro‐/nanoswimmers can be actuated and steered in a fuel‐free manner using a low‐strength rotating magnetic field, generating remotely controlled 3D locomotion with high precision in a variety of biofluidic environments. They are therefore envisioned for biomedical applications related to targeted diagnosis and therapy. In this article, a porous hollow microswimmer possessing an outer shell aggregated by mesoporous spindle‐like magnetite nanoparticles (NPs) and a helical‐shaped inner cavity is proposed. The fabrication is straightforward via a cost‐effective mass‐production process of biotemplated synthesis using helical microorganisms. Here, Spirulina‐based fabrication is demonstrated as an example. The fabricated microswimmers are superparamagnetic and exhibit low cytotoxicity. They are also capable of performing structural disassembly to form individual NPs using ultrasound when needed. For the first time in the literature of helical microswimmers, a porous hollow architecture is successfully constructed, achieving an ultrahigh specific surface area for surface functionalization and enabling diffusion‐based cargo loading/release. Furthermore, experimental and analytical results indicate better swimming performance of the microswimmers than the existing non‐hollow helical micromachines of comparable sizes and dimensions. These characteristics of the as‐proposed microswimmers suggest a novel microrobotic tool with high loading capacity for targeted delivery of therapeutic/imaging agents in vitro and in vivo.     

Light‐Triggered Clustered Vesicles with Self‐Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy against Hypoxic Tumor

Smart nanocarriers are of particular interest for highly effective photodynamic therapy (PDT) in the field of precision nanomedicine. Nevertheless, a critical challenge still remains in the exploration of potent PDT treatment against hypoxic tumor. Herein, light‐triggered clustered polymeric vesicles for photoinduced hypoxic tumor ablation are demonstrated, which are able to deeply penetrate into the tumor and simultaneously afford oxygen supply upon light irradiation. Hydrogen peroxide (H₂O₂) and poly(amidoamine) dendrimer conjugating chlorin e6/cypate (CC‐PAMAM) are coassembled with reactive‐oxygen‐species‐responsive triblock copolymer into the polymeric vesicles. Upon 805 nm irradiation, the vesicles exhibit the light‐triggered thermal effect that is able to decompose H₂O₂ into O₂, which distinctly ensures the alleviation of tumor hypoxia at tumor. Followed by 660 nm irradiation, the vesicles are rapidly destabilized through singlet oxygen‐mediated cleavage of copolymer under light irradiation and thus allow the release of photoactive CC‐PAMAM from the vesicular chambers, followed by their deep penetration in the poorly permeable tumor. Consequently, the light‐triggered vesicles with both self‐supplied oxygen and deep tissue penetrability achieve the total ablation of hypoxic hypopermeable pancreatic tumor through photodynamic damage. These findings represent a general and smart nanoplatform for effective photoinduced treatment against hypoxic tumor.     

Fabricating Aptamer‐Conjugated PEGylated‐MoS2/Cu1.8S Theranostic Nanoplatform for Multiplexed Imaging Diagnosis and Chemo‐Photothermal Therapy of Cancer

Fabricating theranostic nanoparticles combining multimode disease diagnosis and therapeutic has become an emerging approach for personal nanomedicine. However, the diagnostic capability, biocompatibility, and therapeutic efficiency of theranostic nanoplatforms limit their clinic widespread applications. Targeting to the theme of accurate diagnosis and effective therapy of cancer cells, a multifunctional nanoplatform of aptamer and polyethylene glycol (PEG) conjugated MoS₂ nanosheets decorated with Cu_1.8S nanoparticles (ATPMC) is developed. The ATPMC nanoplatform accomplishes photoluminescence imaging, photoacoustic imaging, and photothermal imaging for in vitro and in vivo tumor cells imaging diagnosis. Meanwhile, the ATPMC nanoplatform facilitates selective delivery of gene probe to detect intracellular microRNA aberrantly expressed in cancer cells and anticancer drug doxorubicin (DOX) for chemotherapy. Moreover, the synergistic interaction of MoS₂ and Cu_1.8S renders the ATPMC nanoplatform with superb photothermal conversion efficiency. The ATPMC nanoplatform loaded with DOX displays near‐infrared laser‐induced programmed chemotherapy and advanced photothermal therapy, and the targeted chemo‐photothermal therapy presents excellent antitumor efficiency.     

Nanoscale‐Coordination‐Polymer‐Shelled Manganese Dioxide Composite Nanoparticles: A Multistage Redox/pH/H2O2‐Responsive Cancer Theranostic Nanoplatform

Nanoscale coordination polymers (NCPs) self‐assembled from metal ions and organic bridging ligands exhibit many unique features promising for applications in nanomedicine. In this work, manganese dioxide (MnO₂) nanoparticles stabilized by bovine serum albumin are encapsulated by NCP‐shells constructed based on high‐Z element hafnium (Hf) ions and c,c,t‐(diamminedichlorodisuccinato)Pt(IV) (DSP), a cisplatin prodrug. After further modification with polyethylene glycol (PEG), the formed BM@NCP(DSP)‐PEG can simultaneously serve as a radio‐sensitizer owing to the strong X‐ray attenuation capability of Hf to enhance radiotherapy, as well as a chemotherapeutic agent resulting from the reduction‐induced release of cisplatin. Meanwhile, the in situ generated oxygen resulting from MnO₂‐triggered decomposition of tumor endogenous H₂O₂ will be greatly helpful for overcoming hypoxia‐associated radio‐resistance. Upon intravenous injection, BM@NCP(DSP)‐PEG shows efficient tumor homing as well as rapid renal excretion, as illustrated by magnetic resonance imaging and confirmed by biodistribution measurement. Notably, an excellent in vivo tumor growth inhibition effect is observed with BM@NCP(DSP)‐PEG nanoparticles after the combined chemoradiotherapy treatment. Therefore, the NCP‐based composite nanoparticles with inherent biodegradability and no appreciable in vivo toxicity may be a unique type of multifunctional nanoplatform responsive to different parameters in the tumor microenvironment, promising for cancer theranostics with great efficacy.     

An O2 Self‐Sufficient Biomimetic Nanoplatform for Highly Specific and Efficient Photodynamic Therapy

Conventional oxygen‐dependent photodynamic therapy (PDT) has faced severe challenges because of the non‐specificity of most available photosensitizers (PSs) and the hypoxic nature of tumor tissues. Here, an O₂ self‐sufficient cell‐like biomimetic nanoplatform (CAT‐PS‐ZIF@Mem) consisting of the cancer cell membrane (Mem) and a cytoskeleton‐like porous zeolitic imidazolate framework (ZIF‐8) with the embedded catalase (CAT) protein molecules and Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS₄, defined as PS) is developed. Because of the immunological response and homologous targeting abilities of the cancer cell membrane, CAT‐PS‐ZIF@Mem is selectively accumulated at the tumor site and taken up effectively by tumor cells after intravenous injection. After the intracellular H₂O₂ penetration into the framework, it is catalyzed by CAT to produce O₂ at the hypoxic tumor site, facilitating the generation of toxic ¹O₂ for highly effective PDT in vivo under near‐infrared irradiation. By integrating the immune escape, cell homologous recognition, and O₂ self‐sufficiency, this cell‐like biomimetic nanoplatform demonstrates highly specific and efficient PDT against hypoxic tumor cells with much reduced side‐effect on normal tissues.     

Biodegradable Fe(III)@WS2‐PVP Nanocapsules for Redox Reaction and TME‐Enhanced Nanocatalytic,Photothermal, and Chemotherapy

In this study, biocompatible Fe(III) species‐WS₂‐polyvinylpyrrolidone (Fe(III) @ WS₂‐PVP) nanocapsules with enhanced biodegradability and doxorubicin (DOX) loading capacity are one‐pot synthesized. In this nanocapsule, there exists a redox reaction between Fe(III) species and WS₂ to form Fe²⁺ and WO₄^2?. The formed Fe²⁺ could be oxidized to Fe³⁺, which reacts with Fe(III) @ WS₂‐PVP again to continuously produce Fe²⁺ and WO₄^2?. Such a repeated endogenous redox reaction leads to an enhanced biodegradation and DOX release of DOX @ Fe(III) @ WS₂‐PVP. More strikingly, the Fe²⁺ generation and DOX release are further accelerated by the overexpressed H₂O₂ and the mild acidic tumor microenvironment (TME), since H₂O₂ and H⁺ can accelerate the oxidation of Fe²⁺. The continuously generated Fe²⁺ catalyzes a fast Fenton reaction with the innate H₂O₂ in tumor cells and produces abundant highly toxic hydroxyl radicals for nanocatalytic tumor therapy. Together with the high photothermal transforming capability, the DOX @ Fe(III) @WS₂‐PVP nanocapsules successfully achieve the endogenous redox reaction and exogenous TME‐augmented tumor photothermal therapy, chemo and nanocatalytic therapy outcome. The concept of material design can be innovatively extended to the synthesis of biodegradable Fe(III) @ MoS₂‐PVP nanocomposite, thus paving a promising novel way for the rational design of intelligent theranostic agents for highly efficient treatment of cancer.     

An Ultrasmall SnFe2O4 Nanozyme with Endogenous Oxygen Generation and Glutathione Depletion for Synergistic Cancer Therapy

The tumor microenvironment (TME) with the characteristics of severe hypoxia, overexpressed glutathione (GSH), and high levels of hydrogen peroxide (H₂O₂) dramatically limits the antitumor efficiency by monotherapy. Herein, a novel TME-modulated nanozyme employing tin ferrite (SnFe₂O₄, abbreviated as SFO) is presented for simultaneous photothermal therapy (PTT), photodynamic therapy (PDT), and chemodynamic therapy (CDT). The as-fabricated SFO nanozyme demonstrates both catalase-like and GSH peroxidase-like activities. In the TME, the activation of H₂O₂ leads to the generation of hydroxyl radicals (•OH) in situ for CDT and the consumption of GSH to relieve antioxidant capability of the tumors. Meanwhile, the nanozyme can catalyze H₂O₂ to generate oxygen to meliorate the tumor hypoxia, which is beneficial to achieve better PDT. Furthermore, the SFO nanozyme irradiated with 808 nm laser displays a prominent phototherapeutic effect on account of the enhanced photothermal conversion efficiency (η  = 42.3%) and highly toxic free radical production performance. This “all in one” nanozyme integrated with multiple treatment modalities, computed tomography, and magnetic resonance imaging properties, and persistent modulation of TME exhibits excellent tumor theranostic performance. This strategy may provide a new dimension for the design of other TME-based anticancer strategies.     

Biodegradable Calcium Phosphate Nanotheranostics with Tumor-Specific Activatable Cascade Catalytic Reactions-Augmented Photodynamic Therapy

Photodynamic therapy (PDT) is exploited as a promising strategy for cancer treatment. However, the hypoxic solid tumor and the lack of tumor-specific photosensitizer administration hinder the further application of oxygen (O₂)-dependent PDT. In this study, a biodegradable and O₂ self-supplying nanoplatform for tumor microenvironment (TME)-specific activatable cascade catalytic reactions-augmented PDT is reported. The nanoplatform (named GMCD) is constructed by coloading catalase (CAT) and sinoporphyrin sodium (DVDMS) in the manganese (Mn)-doped calcium phosphate mineralized glucose oxidase (GOx) nanoparticles. The GMCD can effectively accumulate in tumor sites to achieve an “off to on” fluorescence transduction and a TME-activatable magnetic resonance imaging. After internalization into cancer cells, the endogenous hydrogen peroxide (H₂O₂) can be catalyzed to generate O₂ by CAT, which not only promotes GOx catalytic reaction to consume more intratumoral glucose, but also alleviates tumor hypoxia and enhances the production of cytotoxic singlet oxygen from light-triggered DVDMS. Moreover, the H₂O₂ generated by GOx-catalysis can be converted into highly toxic hydroxyl radicals by Mn²⁺-mediated Fenton-like reaction, further amplifying the oxidative damage of cancer cells. As a result, GMCD displays superior therapeutic effects on 4T1-tumor bearing mice by a long term cascade catalytic reactions augmented PDT.     

An Integrated Multifunctional Nanoplatform for Deep‐Tissue Dual‐Mode Imaging

The combination of biocompatible superparamagnetic and photoluminescent nanoparticles (NPs) is intensively studied as highly promising multifunctional (magnetic confinement and targeting, imaging, etc.) tools in biomedical applications. However, most of these hybrid NPs exhibit low signal contrast and shallow tissue penetration for optical imaging due to tissue‐induced optical extinction and autofluorescence, since in many cases, their photoluminescent components emit in the visible spectral range. Yet, the search for multifunctional NPs suitable for high photoluminescence signal‐to‐noise ratio, deep‐tissue imaging is still ongoing. Herein, a biocompatible core/shell/shell sandwich structured Fe₃O₄@SiO₂@NaYF₄:Nd³⁺ nanoplatform possessing excellent superparamagnetic and near‐infrared (excitation) to near‐infrared (emission), i.e., NIR‐to‐NIR photoluminescence properties is developed. They can be rapidly magnetically confined, allowing the NIR photoluminescence signal to be detected through a tissue as thick as 13 mm, accompanied by high T₂ relaxivity in magnetic resonance imaging. The fact that both the excitation and emission wavelengths of these NPs are in the optically transparent biological windows, along with excellent photostability, fast magnetic response, significant T₂‐contrast enhancement, and negligible cytotoxicity, makes them extremely promising for use in high‐resolution, deep‐tissue dual‐mode (optical and magnetic resonance) in vivo imaging and magnetic‐driven applications.