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.     

Reactive Oxygen Species–Activatable Liposomes Regulating Hypoxic Tumor Microenvironment for Synergistic Photo/Chemodynamic Therapies

Tumors have adapted various cellular antidotes and microenvironmental conditions to subsist against photodynamic therapy (PDT) and chemodynamic therapy (CDT). Here, the development of reactive oxygen species (ROS)‐activatable liposomes (RALP) for therapeutic enhancement by simultaneously addressing the critical questions in PDT and CDT is reported. The design of RALP@HOC@Fe₃O₄ features ROS‐cleavable linker molecules for improved tumor penetration/uptake and ondemand cargo releasing, and integration of Fe₃O₄ and an oxaliplatin prodrug for smart regulation of hypoxia tumor microenvironment. Glutathione stored by the tumor cells is consumed by the prodrug to produce highly toxic oxaliplatin. Depletion of glutathione not only avoids the undesired annihilation of ROS in PDT, but also modulates the chemical specie equilibria in tumors for H₂O₂ promotion, leading to greatly relieved tumor hypoxia and PDT enhancement. Synergistically, Fe (II) in the hybrid RALP formulation can be fuelled by H₂O₂ to generate ?OH in the Fenton reaction, thus elevating CDT efficiency. This work offers a strategy for harnessing smart, responsive, and biocompatible liposomes to enhance PDT and CDT by regulating tumor microenvironment, highlighting a potential clinical translation beneficial to patients with cancer.     

Tumor Microenvironment-Responsive Nanocarrier Based on VOx Nanozyme Amplify Oxidative Stress for Tumor Therapy

The construction of a novel nanocarrier that can break the redox balance in tumor cell is a promising anti-tumor strategy. Herein, a tumor microenvironment (TME)-responsive nanocarrier VC@Lipo is rationally designed by embedding ultrasmall VO_x nanozyme and photosensitizer chlorin e6 (Ce6) into liposomes. The size of VC@Lipo nanocarrier is ≈35 nm and can be degraded in the weakly acidic environment of TME. The VO_x nanozyme exhibits peroxidase-like activity and generates highly toxic hydroxyl radical ∙OH through Fenton-like reaction and ¹O₂ in the presence of H₂O₂ independent of light, and more ¹O₂ can be generated by the photodynamic effect of Ce6. In addition, the VO_x nanozyme can effectively deplete intracellular overexpressed glutathione (GSH) through redox reactions. In vivo experiments demonstrate that the nanocarrier shows excellent biocompatibility, presents the largest enrichment at the tumor site after 6 h of intravenous injection into mice with the highest tumor inhibition rate of 54.18% after laser irradiation. Compared with the single treatment mode, VC@Lipo shows the best synergistic effect of chemodynamic-photodynamic therapy. This work provides a new paradigm for nanocatalytic therapy of cancer and is expected to provide new ideas for precision medicine in cancer.     

A Robust ROS Generation Strategy for Enhanced Chemodynamic/Photodynamic Therapy via H2O2/O2 Self-Supply and Ca2+ Overloading

The efficacy of cancer therapy with reactive oxygen species (ROS) as the main therapeutic medium suffers from a deficiency of oxy-substrates, for example, insufficient endogenous hydrogen peroxide (H₂O₂) in chemodynamic therapy (CDT) and inherent hypoxia in photodynamic therapy (PDT). Herein, a smart polyethylene glycol (PEG)-ylated nanosystem CaO₂@ZIF-Fe/Ce6@PEG (abbreviation as CaZFCP) is constructed to achieve H₂O₂/O₂ self-supply and Ca²⁺ overloading in tumor cells simultaneously for enhanced CDT/PDT. Under the weakly acidic tumor microenvironment, the activity components inside CaZFCP, that is, CaO₂ nanoparticles, Fe²⁺, and photosensitizer Chlorin e6 (Ce6) are released by the degradation of zeolitic imidazole framework-90 (ZIF-90). Thereinto, CaO₂ nanoparticles are further decomposed to generate H₂O₂ and O₂, which alleviates both the insufficient endogenous H₂O₂ and hypoxia in tumor area, thus enhancing the efficiency of CDT and PDT by producing more hydroxyl radicals and singlet oxygen. Furthermore, Ca²⁺ overloading induced by the decomposition of CaO₂ is available for amplifying intracellular oxidative stress, resulting in mitochondrial dysfunction, which further improves the efficacy of combined CDT/PDT. In vitro and in vivo experimental results confirm excellent tumor inhibition effect, which also provides a facile paradigm in ROS-involved cancer therapies.     

Mixed-Metal MOF-Derived Hollow Porous Nanocomposite for Trimodality Imaging Guided Reactive Oxygen Species-Augmented Synergistic Therapy

Here an excellent trimodality imaging-guided synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT) is proposed. To this end, a mixed-metal Cu/Zn-metal-organic framework (MOF) is first assembled at room temperature on a nano-scale. Interestingly, heating the MOF results in a Cu^+/2+-coexisting hollow porous structure. Subsequent heating treatment is used to integrate Mn²⁺ and MnO₂ in the presence of manganese(II) acetylacetonate. The hollow composite achieves efficient loading of a photosensitizer, indocyanine green (ICG). Under laser irradiation, the aggregated ICG achieves photothermal imaging and PTT. Once released in the tumor site, ICG exhibits fluorescence imaging and PDT capacity. Cu⁺/Mn²⁺ ions perform Fenton-like reaction with H₂O₂ to produce cytotoxic •OH for the enhanced CDT. Cu²⁺/MnO₂ scavenge glutathione to improve the reactive oxygen species-based therapy, while the formed Mn²⁺ ions enable “turn on” magnetic resonance imaging. Significantly, O₂ is produced from the catalytic decomposition of endogenous H₂O₂ to improve ICG-mediated PDT. Moreover, photothermal-induced local hyperthermia accelerates •OH generation to enhance CDT. This synergistic drug-free antitumor strategy realizes high treatment efficacy and low side effects on normal tissues. Thus, this mixed-metal MOF is an efficient strategy to realize hollow structures for multi-function integration to improve therapeutic capacity.     

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.     

In Situ Polymerized Hollow Mesoporous Organosilica Biocatalysis Nanoreactor for Enhancing ROS‐Mediated Anticancer Therapy

The combination of reactive oxygen species (ROS)‐involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS‐mediated cancer treatment. Herein, an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor is reported to integrate the synergistic effect of PDT/CDT for enhancing ROS‐mediated pancreatic ductal adenocarcinoma treatment. 2‐(1‐hexyloxyethyl)‐2‐devinylpyropheophorbide‐a photosensitizer is hybridized within the framework of HMON via an “in situ framework growth” approach. Then, the hollow cavity of HMONs is exploited as a nanoreactor for “in situ polymerization” to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase‐like nanozyme, converting glucose into H₂O₂ to provide self‐supplied H₂O₂ for CDT. Meanwhile, Cu²⁺‐tannic acid complexes are further deposited on the surface of HMONs (HMON‐Au@Cu‐TA) to initiate Fenton‐like reaction to covert the self‐supplied H₂O₂ into ?OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix, is loaded into HMON‐Au@Cu‐TA to enhance the penetration of HMONs and O₂ infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS‐mediated antitumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.     

GSH‐Depleted PtCu3 Nanocages for Chemodynamic‐ Enhanced Sonodynamic Cancer Therapy

The ultrahigh concentration of glutathione (GSH) inside tumors destroys reactive oxygen species (ROS)‐based therapy, improving the outcome of chemodynamic therapy (CDT)‐enhanced sonodynamic therapy (SDT) by depleting GSH is full of great challenge. Herein, PtCu₃ nanocages are first reported as acting as a sonosensitizer with highly efficient ROS generation under ultrasound irradiation. In addition, PtCu₃ nanocages can act as horseradish peroxidase‐like nanozymes, catalyzing the decomposition of H₂O₂ into ^?OH under acidic conditions for CDT. Surprisingly, PtCu₃ nanocages can act as another kind of nanozyme, mimicking glutathione peroxidase (GSH‐Px), which plays an important role in accelerating GSH depletion by oxidizing molecules, further weakening the capacity of tumor cells scavenging ROS by GSH. Both in vitro and in vivo studies demonstrate that PtCu₃ nanocages perform well in reducing GSH level for CDT‐enhanced SDT. Moreover, utilizing the high absorption in the near‐infrared region and strong X‐ray attenuation ability, the PtCu₃ nanocages are able to conduct photoacoustic/computed tomography dual‐modal imaging‐guided combined cancer therapy. It is worth mentioning that PtCu₃ nanocages cause minimal toxicity to normal tissues at therapeutic doses. This work highlights the use of PtCu₃ nanocages for effective CDT‐enhanced SDT via GSH depletion.     

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.     

Phase‐Change Materials Based Nanoparticles for Controlled Hypoxia Modulation and Enhanced Phototherapy

Tumor hypoxia strengthens tumor resistance to different therapies especially oxygen involved strategies, such as photodynamic therapy (PDT). Herein, the thermal responsive phase change materials (PCM) are utilized to coencapsulate ultrasmall manganese dioxide (sMnO₂) and organic photosensitizer IR780 to obtain IR780‐sMnO₂‐PCM nanoparticles for controlled tumor hypoxia modulation and enhanced phototherapy. The thermal responsive protective PCM layer can not only prevent IR780 from photodegradation, but also immediately release sMnO₂ to decompose endogenous H₂O₂ and generate enough oxygen for PDT under laser irradiation. Owing to the efficient accumulation of IR780‐sMnO₂‐PCM nanoparticles in tumor under intravenous injection as revealed by both florescence imaging and photoacoustic imaging, the tumor hypoxia is greatly relieved. Furthermore, in vivo combined photothermal therapy (PTT) and PDT, IR780‐sMnO₂‐PCM nanoparticles, compared to IR780‐PCM nanoparticles, exhibit better performance in inhibiting tumor growth. The results highlight the promise of IR780‐sMnO₂‐PCM in controlled modulation of tumor hypoxia to overcome current limitations of cancer therapies.     

Recent Advances in Nanomaterial-Based Nanoplatforms for Chemodynamic Cancer Therapy

Triggered by the endogenous chemical energy in the tumor microenvironment (TME), chemodynamic therapy (CDT) as an emerging non-exogenous stimulant therapeutic modality has received increasing attention in recent years. The chemodynamic agents can convert internal hydrogen peroxide (H₂O₂) into the lethal reactive oxygen species (ROS) hydroxyl radicals (^•OH) for oncotherapy. Compared with other therapeutic modalities, CDT possesses many notable advantages, such as tumor-specific, highly selective, fewer systemic side effects, and no need for external stimulation. Nevertheless, mild acid pH, low H₂O₂ content, and overexpressed reducing substance in TME severely suppressed the CDT efficiency. With the rapid development of nanotechnology, some kinds of nanomaterials have been utilized with improved CDT efficiency. In particular, the excellent photo-, ultrasound-, magnetic-, and other stimuli-response properties of nanomaterials make it possible for combination cancer therapy of CDT with other therapeutic modalities, and it has shown superior anti-cancer activity than monotherapies. Therefore, it is necessary to summarize the application of nanomaterial-based chemodynamic cancer therapy. In this review, the various nanomaterials-based nanoplatforms for CDT and its combinational therapies are summarized and discussed, aiming to provide inspiration for the design of better-quality agents to promote the CDT development and lay the foundation for its future conversion to clinical applications.     

Self-Amplified Competitive Coordination of MnO2-Doped CeO2 Nanozyme for Synchronously Activated Combination Therapy

Tumor-specific combination therapy has shown great promise in cancer theranostics. However, the therapeutic efficacy is usually suppressed because most of the therapeutic systems are not able to synchronously activate their different therapeutic approaches and the local concentration of tumor-associated stimulus is generally insufficient to fully activate the combination therapy process. Herein, a MnO₂-doped CeO₂ nanozyme-based nanomedicine (Ce6@CMNRs) is reported for tumor-specific synchronously activated chemodynamic/photodynamic combination therapy. The tumor-overexpressed H₂O₂ substitutes the Ce6 on Ce6@CMNRs surfaces via competitive coordination and then decomposes into •OH under acidic condition, achieving the chemodynamic therapy (CDT). Meanwhile, the substituted Ce6 triggers photodynamic therapy (PDT) under laser irradiation that is suppressed before the substitution occurs. Thus, H₂O₂ can synchronously activate both CDT and PDT of Ce6@CMNRs with a similar level in tumor sites. Moreover, the activated PDT-induced oxygen starvation further triggers the generation of H₂O₂ to continuously replace the residual Ce6 coordinated on the nanorod surface, thereby leading to the full activation of PDT and CDT. Also, the doped MnO₂ enhances the generation of •OH and provides high contrast for magnetic resonance imaging (MRI) with the help of glutathione. Therefore, Ce6@CMNRs are promising candidates for MRI-guided CDT/PDT combination therapy with minimized side effects and high efficiency.     

In Situ Nanozyme-Amplified NIR-II Phototheranostics for Tumor-Specific Imaging and Therapy

The discovery of near-IR-II (NIR-II) tumor phototheranostics holds a great promise for use in nanomedicine on account of its enhanced penetration depth, high spatial resolution, and noninvasiveness. However, contemporary “always on” phototherapeutic agents often have many undesirable side effects that hinder their clinical trial progress. To overcome this dilemma, an in situ nanozyme-amplified chromogenic nanoreactor by loading 3,3′,5,5′-tetramethylbenzidine (TMB) and ultrasmall PtAu nanoparticles into a metal–organic framework is developed for specific tumor theranostics, leaving normal tissues unharmed. As an intelligent photoacoustic diagnostic agent, the as-constructed nanoreactor remains silent until they enter the tumor site (H₂O₂-activated and acid-enhanced conditions) and turns on the photoacoustic signal to render a preoperative tumor diagnosis. As a nanozyme, the special microenvironment of the tumor tissue is used to initiate its catalytic damage by reactive oxygen species for chemodynamic therapy (CDT). More importantly, the TMB is oxidized, and the subsequent photothermal therapy (PTT) can be realized, leading to an optimal combination of CDT and PTT to concurrently fight obstinate cancers. The present “all-in-one” phototheranostics utilize nanozyme-augmented NIR-II agents for specific tumor ablation, which are promising for further development of intelligent nanozymes in tumor therapy.     

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.     

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.     

Glutathione‐Activatable and O2/Mn2+‐Evolving Nanocomposite for Highly Efficient and Selective Photodynamic and Gene‐Silencing Dual Therapy

Photodynamic therapy (PDT) has been applied in cancer treatment by converting O₂ into reactive singlet oxygen (¹O₂) to kill cancer cells. However, the effectiveness of PDT is limited by the fact that tumor hypoxia causes an inadequate O₂ supply, and the overexpressed glutathione (GSH) in cancer cells consumes reactive oxygen species. Herein, a multifunctional hybrid system is developed for selective and highly efficient PDT as well as gene‐silencing therapy using a novel GSH‐activatable and O₂/Mn²⁺‐evolving nanocomposite (GAOME NC). This system consists of honeycomb MnO₂ (hMnO₂) nanocarrier loaded with catalase, Ce6, and DNAzyme with folate label, which can specifically deliver payloads into cancer cells. Once endocytosed, hMnO₂ carriers are reduced by the overexpressed GSH to Mn²⁺ ions, resulting in the reduction of GSH level and disintegration of GAOME NC. The released catalases then trigger the breakdown of endogenous H₂O₂ to generate O₂, which is converted by the excited Ce6 into ¹O₂. The self‐sufficiency of O₂ and consumption of GSH effectively enhance the PDT efficacy. Moreover, DNAzyme is freed for gene silencing in the presence of self‐generated Mn²⁺ ions as cofactors. The rational synergy of enhanced PDT and gene‐silencing therapy remarkably improve the in vitro and in vivo therapeutic efficacy of cancers.     

Synthesis of MoSe2/CoSe2 Nanosheets for NIR-Enhanced Chemodynamic Therapy via Synergistic In-Situ H2O2 Production and Activation

Currently, the limited intratumoral H₂O₂ level restricts the development of chemodynamic therapy (CDT). Herein, MoSe₂/CoSe₂@PEG nanosheets are prepared to reveal NIR-photocatalytic H₂O₂ generation to insure the intracellular H₂O₂ supplement. The formation mechanism is investigated, showing the dissolved O₂ and photo-excited electrons to determine H₂O₂ production via sequential single-electron transfer process. The experimental data and density functional theory calculation further display their typical-II heterostructure, which possesses the effective charge separation and nearly four times H₂O₂ generation than MoSe₂@PEG. In addition, the nanocomposites also reveal the peroxidase/catalase activity, making the in-situ H₂O₂ activation and ·OH generation. And, the O₂ production derived from catalase-mimic activity not only relieves hypoxia but also offers the source for H₂O₂ production. Because of the decreased resistance for charge transfer, MoSe₂/CoSe₂@PEGs also reveal more than three times enzyme-activity for MoSe₂@PEG. With the narrow band gap and high NIR-harvest, MoSe₂/CoSe₂@PEG exhibits the great photothermal converting ability (62.5%). MoSe₂/CoSe₂@PEG reveals the novel biodegradation, and most of them can be eliminated via urine and feces within 2 weeks. Here, the computed tomography/magnetic resonance imaging/photothermal imaging and the synergistic photothermal therapy/CDT treatments further make sure potential application on anticancer.     

Black Phosphorus Quantum Dots Encapsulated Biodegradable Hollow Mesoporous MnO2: Dual-Modality Cancer Imaging and Synergistic Chemo-Phototherapy

To achieve an accurate diagnosis and efficient tumor treatment, developing a facile and powerful strategy to build multifunctional nanotheranostics is highly desirable. Benefiting from the distinct characteristics of black phosphorus quantum dots (BPQDs), herein, a versatile nanoprobe (H-MnO₂/DOX/BPQDs) is constructed for dual-modality cancer imaging and synergistic chemo-phototherapy. The hollow mesoporous MnO₂ (H-MnO₂) nanoparticles are sequentially decorated with a cationic polymer poly (allylamine hydrochloride) (PAH) and an anionic polymer poly (acrylic acid) (PAA). The obtained H-MnO₂-PAH-PAA is covalently grafted with BPQDs-PEG-NH₂ via a carbodiimide cross-linking reaction and then loaded with anti-cancer drug DOX to form final nanoprobe H-MnO₂/DOX/BPQDs. Under the tumor microenvironment, H-MnO₂/DOX/BPQDs is degraded to release encapsulated functional molecules DOX and BPQDs. DOX acts as the chemotherapy and fluorescence imaging agent, and BPQDs endows the nanoprobe with photodynamic therapy (PDT) and photothermal therapy (PTT) abilities under dual laser irradiation of 630 and 808 nm. H-MnO₂ offers contrasts for magnetic resonance imaging (MRI) and facilitates conversion of endogenous H₂O₂ to oxygen, thereby relieving tumor hypoxia and enhancing PDT efficacy. All in vitro and in vivo results demonstrate that the designed nanoprobe displays dual-modality MRI/FL imaging and synergistic chemotherapy/PDT/PTT, which ultimately enhances the accuracy of cancer diagnosis and therapeutic performance.     

Unveiling the Multiple Tumor-Targeted Impairments of Covalent-Organic Framework-Switched Photothermal Shielding Nanoparticles

Covalent organic framework (COF) receives great attention in biomedical applications due to its variable compositions and ordered structures. However, its targeted design to achieve desirable physiological functions especially for cancer treatments remains elusive. Herein, PEGylated COF with tumor-specific TKD peptide modification is uniformly coated on photothermal mesoporous carbon nanospheres via polyethyleneimine-mediated interface polymerization to construct a multifunctional core-shell nanoparticle (OPCPT). Physicochemical studies demonstrate near infrared (NIR)-blocking ability of the crystalline COF shells under physiological conditions, whereas COF is degraded under the acidic tumor microenvironments (TME). Subsequently, the nanoparticle charge is reversed and the COF monomers can produce ¹O₂/O₂. As a result, OPCPT, activated in the TME due to the shell dissociation, penetrates deeply into tumors through positive charge-mediated/lysosome rupture-mediated transcytosis and recovers its NIR-heating potential for tumor-specific photothermal therapy. Moreover, the TME-triggered ¹O₂ significantly depresses the lysosome autophagy via membrane destruction, and selectively damages the mitochondria to promote the cytochrome C release-activated apoptosis and ATP deficiency-inhibited tumor metastasis. Particularly, this unique O₂ generation mechanism relieves the tumor hypoxia upon the reactive oxygen species therapy and downregulates hypoxia-inducible factor and its downstream proteins, which all contribute to augmented tumor therapy. The findings represent a remarkable unveiling of the potential of COF-based nanomaterials for extended biomedical applications.     

Co–Ferrocene MOF/Glucose Oxidase as Cascade Nanozyme for Effective Tumor Therapy

Chemodynamic therapy (CDT), enabling selective therapeutic effects and low side effect, attracts increasing attention in recent years. However, limited intracellular content of H₂O₂ and acid at the tumor site restrains the lasting Fenton reaction and thus the anticancer efficacy of CDT. Herein, a nanoscale Co–ferrocene metal–organic framework (Co‐Fc NMOF) with high Fenton activity is synthesized and combined with glucose oxidase (GOx) to construct a cascade enzymatic/Fenton catalytic platform (Co‐Fc@GOx) for enhanced tumor treatment. In this system, Co‐Fc NMOF not only acts as a versatile and effective delivery cargo of GOx molecules to modulate the reaction conditions, but also possesses excellent Fenton effect for the generation of highly toxic ?OH. In the tumor microenvironment, GOx delivered by Co‐Fc NMOF catalyzes endogenous glucose to gluconic acid and H₂O₂. The intracellular acidity and the on‐site content of H₂O₂ are consequently promoted, which in turn favors the Fenton reaction of Co‐Fc NMOF and enhances the generation of reactive oxygen species (ROS). Both in vitro and in vivo results demonstrate that this cascade enzymatic/Fenton catalytic reaction triggered by Co‐Fc@GOx nanozyme enables remarkable anticancer properties.