Light-Controlled Nanosystem with Size-Flexibility Improves Targeted Retention for Tumor Suppression

Although great promise has been achieved with nanomedicines in cancer therapy, limitations are still encountered, such as short retention time in the tumor. Herein, a nanosystem that can modulate the particle size in situ by near-infrared (NIR) light is self-assembled by cross-linking the surface-modified poly(lactic-co-glycolic acid) from the up-conversion nanoparticle with indocyanine green and doxorubicin–nitrobenezene–polyethylene glycol (DOX–NB–PEG). The nanosystem with its small size (≈100 nm) achieves better tumor targeting, while the PEG on the surface of the nanosystem can effectively shield the adsorption of proteins during blood circulation, maintaining a stable nanostructure and achieving good tumor targeting. Moreover, the nanosystem at the tumor realizes the rapid shedding of PEG on its surface by NIR irradiation, and the enhanced cellular uptake. At the same time, aggregation occurs inside the nanosystem to form bigger particles (≈600 nm) in situ, prolonging the retention time at the tumor and producing enhanced targeted therapeutic effects. In vitro data show higher cellular uptake and a higher rate of apoptosis after irradiation, and the in vivo data prove that the nanosystem have a longer residence time at the tumor site after NIR irradiation. This nanosystem demonstrates an effective therapeutic strategy in targeted synergistic tumors.     

A Versatile Nanoplatform Based on Metal-Phenolic Networks Inhibiting Tumor Growth and Metastasis by Combined Starvation/Chemodynamic/Immunotherapy

Although much progress has been made by multifunctional nanoplatforms in the treatment of cancer, several defects of existing nanoplatforms, such as tedious preparation, poor biocompatibility, and failure to activate the immune system, have limited their clinical applications. Herein, a versatile nanosystem of folic acid-modified metal-phenolic networks (MPNs) loaded with GOx and CHA (F-MGC) is fabricated by the easy self-assembly of MPNs, during which glucose oxidase (GOx) and chlorogenic acid (CHA) are concurrently loaded. The resulting nanosystem, having a folic acid-modified surface and inherent acid sensitivity, shows versatility in being able to target tumors and release active ingredients in the weakly acidic tumor microenvironment (TME). Based on the catalysis of GOx and Fe³⁺, the cascade reaction aroused by F-MGC efficiently consumes glucose in the TME and produces abundant cytotoxic hydroxyl radicals, thereby causing the starving and chemodynamic death of cancer cells. In addition, CHA can reshape M2 tumor-associated macrophages (TAMs) into the M1 type, so as to change the immunosuppressive state of TME. The immunogenic cell death (ICD) that occurs from the starvation and chemodynamic therapy, in conjunction with the CHA-induced TAMs polarization, further activates the immune system. Overall, the easily prepared nanoplatform has excellent biocompatibility and effectively inhibits tumor growth and metastasis.     

Hyaluronidase with pH‐responsive Dextran Modification as an Adjuvant Nanomedicine for Enhanced Photodynamic‐Immunotherapy of Cancer

The condensed tumor extracellular matrix (ECM) consisting of cross‐linked hyaluronic acid (HA) is one of key factors that results in the aberrant tumor microenvironment (TME) and the resistance to various types of therapies. Herein, hyaluronidase (HAase) is modified by a biocompatible polymer, dextran (DEX), via a pH‐responsive traceless linker. The formulated DEX‐HAase nanoparticles show enhanced enzyme stability, reduced immunogenicity, and prolonged blood half‐life after intravenous injection. With efficient tumor passive accumulation, DEX‐HAase within the acidic TME would be dissociated to release native HAase, which afterward triggers the breakdown of HA to loosen the ECM structure, subsequently leading to enhanced penetration of oxygen and other therapeutic agents. The largely relieved tumor hypoxia would promote the therapeutic effect of nanoparticle‐based photodynamic therapy (PDT), accompanied by the reverse of the immunosuppressive TME to boost cancer immunotherapy. Interestingly, the therapeutic responses achieved by the combination of PDT and anti‐programmed death‐ligand 1 (anti‐PD‐L1) checkpoint blockade therapy could be significantly enhanced by pretreatment with DEX‐HAase. In addition to destructing tumors with direct light exposure, a robust abscopal effect is achieved after such treatment, which is promising for tumor metastasis inhibition. The work presents a new type of adjuvant nanomedicine to assist photodynamic‐immunotherapy of cancer, by effective modulation of TME.     

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.     

Engineered Oxygen Factories Synergize with STING Agonist to Remodel Tumor Microenvironment for Cancer Immunotherapy

Immunotherapy is a revolutionary achievement in cancer treatment. However, inadequate immune cells infiltration in tumor microenvironment (TME) always leads to treatment failure. Moreover, hypoxic TME hampers normal functions of immune cells. Here, it is found that hypoxia suppresses the STING signaling and immune cells activation in the work. Remodeling tumor immune microenvironment and relieving hypoxia are thus essential for enhancing immunotherapy efficiency. Herein, a spirulina platensis (SP)-based magnetic biohybrid system is constructed as an oxygen factory and loaded with stimulator of interferon genes (STING) agonist ADU-S100 (ADU@Fe-SP) for tumor immunotherapy. Magnet-guided biohybrid SP can actively target tumor tissues and produce oxygen in situ through photosynthesis, which reverses the hypoxic TME and facilitates the function of immune cells. Besides, the targeted delivery of ADU-S100 can activate the STING/TBK1/IRF3 signaling and boost cytokines production in tumor and innate immune cells. The ADU@Fe-SP system thus induces efficient immune cells infiltration in TME, which efficiently inhibits tumor progression and significantly enhances anti-PD-1 therapy efficiency in SCC VII-bearing tumor xenograft. ADU@Fe-SP exerts antitumor effect in a STING-dependent manner by in vivo STING-knockout mice model. The efficiency of this immunotherapy strategy is also demonstrated in patient-derived xenograft model originating from oral cancer, showing great clinical potential.     

Light‐Activatable Assembled Nanoparticles to Improve Tumor Penetration and Eradicate Metastasis in Triple Negative Breast Cancer

Triple‐negative breast cancer (TNBC) is a kind of aggressive malignancy with fast metastatic behavior. Herein, a nanosystem loaded with a near‐infrared (NIR) agent is developed to achieve chemo‐photothermal combination therapy for inhibiting tumor growth and metastasis in TNBC. The NIR agent of ultrasmall sized copper sulfide nanodots with strong NIR light‐absorbing capability is entrapped into the doxorubicin‐contained temperature‐sensitive polymer‐based nanosystem by a self‐assembled method. The temperature sensitive nanoclusters (TSNCs) can significantly enhance the drug penetration depth and significantly kill the cancer cells under the near‐infrared laser irradiation. Importantly, it is plausible that the tumor penetrating nanosystem combined with NIR laser irradiation can prevent lung and liver metastasis via extermination of the cancer stem cells. The in vivo characteristics, evaluated by photoacoustic imaging, pharmacokinetics, and biodistribution, confirm their feasibility for tumor treatment owing to their long blood circulation time and high tumor uptake. Thanks to the high tumor uptake and highly potent antitumor efficacy, the doxorubicin‐induced cardiotoxicity can be avoided when the TSNC is used. Taken together, it is believed that the nanosystem has excellent potential for clinical translation.     

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.     

Ferroptosis and Pyroptosis Co-Activated Nanomodulator for “Cold” Tumor Immunotherapy and Lung Metastasis Inhibition

Immune checkpoint blockade (ICB) therapy is an emerging strategy for cancer immunotherapy; however, the actual effects of ICB therapy are greatly limited by the immunosuppressive tumor microenvironment (TME, i.e., “cold” tumors). Although engineered nanomaterials display significant importance to regulate TME in cancer treatment, most of them focus on “immunosilent” apoptotic processes that cannot elicit sufficient immune responses for further immunotherapy. Herein, a GSH-responsive nanomodulator is reported that can reverse the immunosuppressive TME for “cold” tumor immunotherapy and lung metastasis inhibition through simultaneous ferroptosis and pyroptosis induction. The nanomodulator is constructed by loading FDA-approved sulfasalazine (SAS) and doxorubicin (DOX) on disulfide-doped organosilica hybrid micelles, where SAS and DOX are released through the GSH-stimulated rupture of micelles to induce ferroptosis and pyroptosis, respectively, promoting dendritic cells (DCs) maturation and cytotoxic T lymphocytes (CTLs) elevation through massive tumor-associated antigen release. In vivo experimental results verify that desirable tumor destruction of the nanomodulator at low concentrations is achieved. More importantly, combination of this nanomodulator and programed death ligand-1 antibodies significantly inhibits primary tumors and distant lung metastases as a result of elevated mature DCs and CTLs. This strategy to modulate immunosuppressive TME by nanomodulator-induced non-apoptotic death provides a new promising paradigm for ICB therapy.     

Bioactive Bacteria/MOF Hybrids Can Achieve Targeted Synergistic Chemotherapy and Chemodynamic Therapy against Breast Tumors

The hypoxic tumor microenvironment (TME) significantly affects cancer treatment. Conventional chemotherapeutic agents cannot effectively target hypoxic tumor tissue, which decreases efficacy and results in severe toxic side effects. To alleviate this problem, a self-driving biomotor is developed by functionalizing MCDP nanoparticles containing calcium peroxide and doxorubicin (DOX) loaded onto polydopamine-coated metal–organic frameworks（MOF）, with the anaerobic Bifidobacterium infantis (Bif) for synergistic chemotherapy and chemodynamic therapy (CDT) against breast cancer. The materials of institute Lavoisier (MIL) frameworks + CaO₂ + DOX + polydopamine (MCDP)@Bif biohybrid actively targets hypoxic regions of solid tumors via the inherent targeting ability of Bif. Once it has accumulated in the tumor tissue, MCDP generates hydroxyl radicals through the enhanced Fenton-type reactions between Fe²⁺ and self-generated hydrogen peroxide in the acidic TME. The disruption of Ca²⁺ homeostasis and resulting mitochondrial Ca²⁺ overload triggers apoptosis and enhances oxidative stress, promoting tumor cell death. The results found that the DOX concentration in MCDP@Bif-treated tumors is 3.8 times higher than that in free-DOX-treated tumors, which significantly prolongs the median survival of the tumor-bearing mice to 69 days and reduces the toxic side effects of DOX. Therefore, the novel bacteria-driven drug delivery system is highly effective in achieving synergistic chemotherapy and CDT against solid tumors.     

Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo-Immunotherapy

Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe-DOX, is developed, to enhance ICD-mediated antitumor immunity by in situ manipulation of tumor metabolism-immune interactions. The E@Fe-DOX bioreactor is constructed by depositing doxorubicin-loaded iron-polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro-tumoral M2-like macrophages and improves the function of tumor-infiltrating cytotoxic T cells. Furthermore, E@Fe-DOX promotes the formation of immune cell-aggregated tertiary lymph structures (TLS) to augment ICD-induced antitumor immunity. In murine tumor models, E@Fe-DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo-immunotherapy by continuously regulating the intratumoral immuno-metabolic microenvironment.     

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.     

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.     

Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma

O₂‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O₂‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O₂‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O₂‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.     

Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy

Despite the immense potential of immune checkpoint blockade (ICB) therapy in tumor treatment, its widespread clinical application is currently limited by unsatisfactory curative effect and off-target adverse effect. Herein, an injectable sericin (SS)/silk fibroin (SF) recombinant hydrogel, termed SF-SS-SMC hydrogel, is developed to enable local delivery of anti-CD47 antibody (α CD47). The hydrogel displays self-reinforcement in high H₂O₂ concentration of tumor microenvironment (TME), as the SS/Fe²⁺ supramolecular nanocomplex (SS-SMC) inside the hydrogel converts H₂O₂ to reactive oxygen species (ROS), further triggering additional crosslinking among the SF polymers. Therefore, the SF-SS-SMC hydrogel has an in vivo retention time longer than 21 days and acts as a reservoir for the long-term sustained release of α CD47. More importantly, the SF-SS-SMC hydrogel itself efficiently regulates the remodeling of a protumor immunosuppressive TME to an antitumoral TME through switching of tumor-associated macrophages from an anti-inflammatory M2 phenotype to a proinflammatory M1 phenotype without additional drugs. Based on the combined effect of sustained α CD47 release and TME reprogramming, the SF-SS-SMC hydrogel has satisfactory immunotherapeutic effects in the treatment of local, abscopal, remitting, and metastatic tumors. Further advantages, including low cost of production, simple fabrication, and ease of use, make it promising for commercial mass production.     

Photosynthetic Biohybrid Nanoswimmers System to Alleviate Tumor Hypoxia for FL/PA/MR Imaging‐Guided Enhanced Radio‐Photodynamic Synergetic Therapy

Biohybrid microswimmers have recently shown to be able to actively perform in targeted delivery and in vitro biomedical applications. However, more envisioned functionalities of the microswimmers aimed at in vivo treatments are still challenging. A photosynthetic biohybrid nanoswimmers system (PBNs), magnetic engineered bacteria‐Spirulina platensis, is utilized for tumor‐targeted imaging and therapy. The engineered PBNs is fabricated by superparamagnetic magnetite (Fe₃O₄ NPs) via a dip‐coating process, enabling its tumor targeting ability and magnetic resonance imaging property after intravenous injection. It is found that the PBNs can be used as oxygenerator for in situ O₂ generations in hypoxic solid tumors through photosynthesis, modulating the tumor microenvironment (TME), thus improving the effectiveness of radiotherapy (RT). Furthermore, the innate chlorophyll released from the RT‐treated PBNs, as a photosensitizer, can produce cytotoxic reactive oxygen species under laser irradiation to achieve photodynamic therapy. Excellent tumor inhibition can be realized by the combined multimodal therapies. The PBNs also possesses capacities of chlorophyll‐based fluorescence and photoacoustic imaging, which can monitor the tumor therapy and tumor TME environment. These intriguing properties of the PBNs provide a promising microrobotic platform for TME hypoxic modulation and cancer theranostic applications.     

Transcytosis Mediated Deep Tumor Penetration for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer

The hyperproliferative tumor stroma of pancreatic ductal adenocarcinoma (PDAC) severely limits drug permeation and constructs an immunosuppressive microenvironment, causing resistance to chemotherapy and immunotherapy. Traditional nanomedicine mainly focuses on manipulating nanoparticles’ particle size or electrical characteristics to penetrate deep PDAC through the paracellular pathway, but the transcellular pathway is often ignored. Therefore, a versatile drug-polymer conjugate PODEA-Gem-HMI is prepared and assembled into nanoparticles for the codelivery of chemotherapy drug gemcitabine and focal adhesion kinase (FAK) inhibitor defactinib. While sensing the mild acidity in the tumor microenvironment, the nanoparticle will disintegrate and release defactinib to modulate the tumor stroma. The PODEA block of the conjugate can bind with cell membranes reversibly and trigger adsorption-mediated transcytosis (AMT) for promoted tumor penetration and cellular uptake. The internalized conjugates will release gemcitabine responding to the overexpressed glutathione (GSH) for enhanced chemotherapy, and PHMI can condensate the STING monomers for prolonged spontaneous immune stimulation.     

Cascade-Responsive “Oxidative Stress Amplifiers” Simultaneously Destroy Lysosomes and Co-Deliver CRISPR/Cas9 to Enhance Oxidative Damage in Tumor

Amplifying intracellular oxidative stress by organelle-targeted reactive oxygen species (ROS) production combined with tumor cell-specific gene disruption is a promising strategy for tumor treatment. However, due to the vulnerability of CRISPR/Cas9 ribonucleoproteins (RNPs) to ROS, co-delivery of CRISPR/Cas9 RNPs and ROS generators to enhance the sensitivity of tumor cells to oxidative stress remains challenging. Herein, a cascade-responsive “oxidative stress amplifier” (named DR-TAF-pHT/FA) is proposed, which can successively respond to cathepsin B, localized laser irradiation and ATP to generate ROS on the lysosomal membrane of tumor cells and release Cas9/sgNrf2 RNPs for efficient gene disruption. It is demonstrated that, under near infrared (NIR) irradiation, DR-TAF-pHT/FA achieves targeted rupture of lysosomal membranes, inducing significant intracellular oxidative stress. Meanwhile, due to the protective function of TAF coating (TA-Fe³⁺ coordination self-assembled networks), Cas9/sgNrf2 RNPs can safely escape into the cytoplasm and be released in response to ATP, further amplifying oxidative stress and promoting tumor cell apoptosis through efficient Nrf2 gene disruption. Treatment with DR-TAF-pHT/FA + NIR significantly improves tumor ablation efficiency and extends median survival time (over 70 days) in Hela xenograft models. This “oxidative stress amplifier” provides a new paradigm for multimodal and synergistic tumor therapy through precise lysosomal membrane bursting together with efficient Nrf2 gene disruption.     

Self-Reliant Nanomedicine with Long-Lasting Glutathione Depletion Ability Disrupts Adaptive Redox Homeostasis and Suppresses Cancer Stem Cells

Bulk cancer cells and cancer stem cells (CSCs) harbor efficient and adaptive redox systems to help them resist oxidative insults arising from diverse therapeutic modalities. Herein, a tumor microenvironment (TME)-activatable nano-modulator capable of disrupting adaptive redox homeostasis, prepared by integrating FDA-approved xCT inhibitor sulfasalazine (SSZ) into pH-responsive hydroxyethyl starch-doxorubicin conjugate stabilized copper peroxide nanoparticles (HSCPs) is reported. Compared to poly(vinylpyrrolidone) (PVP)-stabilized copper peroxide nanoparticles, HSCPs exhibit superior physiological stability, longer circulation half-life, and higher tumor enrichment. Under an acidic TME, the active components inside HSCPs are productively released along with the disintegration of HSCPs. The specifically generated hydrogen peroxide (H₂O₂) from copper peroxide nanoparticles furnishes a constant power source for copper-mediated hydroxyl radical (•OH) production, serving as a wealthy supplier for oxidative stress. Meanwhile, the tumor-specific release of Cu²⁺ and SSZ can induce long-lasting glutathione (GSH) depletion via copper-mediated self-cycling valence transitions and SSZ-blocked GSH biosynthesis, thereby reducing the offsetting action of the antioxidant GSH against oxidative stress. As a result, this sustained oxidative stress potently restrains the growth of aggressive orthotopic breast tumors while suppressing pulmonary metastasis by eradicating CSC populations. The reported smart nanomedicine provides a new paradigm for redox imbalance-triggered cancer therapy.     

Development of Sulfonamide-Functionalized Charge-Reversal AIE Photosensitizers for Precise Photodynamic Therapy in the Acidic Tumor Microenvironment

Tumor-targeted photodynamic therapy (PDT) is desirable as it can achieve efficient killing of tumor cells with no or less harm to normal cells. Herein, a facile molecular engineering strategy is developed for photosensitizers (PSs) with aggregation induced emission (AIE) characteristics and responsive properties to the acidic tumor microenvironment (TME). By the marriage of pH-sensitive sulfonamide moieties with AIE PSs, two near-infrared AIE luminogens called DBP-SPy and DBP-SPh are designed and synthesized. Both luminogens can form negatively charged nanoaggregates in the aqueous medium at physiological pH. The DBP-SPy nanoaggregates undergo surface charge conversion to become positive at pH close to the signature pH of TME, while DBP-SPh nanoaggregates show no such property. The endowed response to acidic TME enables the enhanced cellular uptake of DBP-SPy at pH = 6.8. By contrast, its cellular uptake is much sacrificed at pH 7.4. As a result, under white light irradiation, DBP-SPy nanoaggregates demonstrate a considerable photodynamic therapeutic effect on cancer cells in vitro and excellent tumor growth inhibition in vivo. Hence, this study not only provides an acidic TME-responsive AIE PS for precise PDT, but also inspires new design strategies for AIE-based theragnostic systems with targeting characteristics.     

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.