Precise Regulation of Reactive Oxygen Species in Tumor Microenvironment for Alleviating Inhibitory Immunogenic Cell Death.

High level of C (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.

A universal nanoreactor triggering butterfly effect for encouraging Fenton/Fenton-like reactions and chemodynamic therapy.

Fenton/Fenton-like reaction induced chemical dynamic therapy (CDT) has been widely recognized in tumor therapy. Due to the low efficiency of conversion from high-valent metal ions (M(n+1)+) to low-valent ions (Mn+) in the Fenton/Fenton-like catalytic process, enhancing the conversion efficiency safely and effectively would create a great opportunity for the clinical application of CDT. In the study, a universal nanoreactor (NR) consisting of liposome (Lip), tumor cell membrane (CM), and bis(2,4,5-trichloro-6-carboxyphenyl) oxalate (CPPO) is developed to tackle this challenge. The CPPO was first discovered to decompose under weak acidity and H2O2 conditions to generate carboxylic acids (R'COOH) and alcohols (R'OH) with reducibility, which will reduce M(n+1)+ to Mn+ and magnify the effect of CDT. Furthermore, glucose oxidase (GOx) was introduced to decompose glucose in tumor and generate H2O2 and glucose acid, which promote the degradation of CPPO, further strengthening the efficiency of CDT, leading to a butterfly effect. This demonstrated that the butterfly effect triggered by NR and GOx encourages Fenton/Fenton-like reactions of Fe3O4 and MoS2, thereby enhancing the tumor inhibition effect. The strategy of combining GOx and CPPO to strengthen the Fenton/Fenton-like reaction is a universal strategy, which provides a new and interesting perspective for CPPO in the application of CDT, reflecting the exquisite integration of Fenton chemistry and catalytic medicine.

Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis.

BACKGROUND: Elevated interstitial fluid pressure within tumors, resulting from impaired lymphatic drainage, constitutes a critical barrier to effective drug penetration and therapeutic outcomes. RESULTS: In this study, based on the photosynthetic characteristics of algae, an active drug carrier (CP@ICG) derived from Chlorella pyrenoidosa (CP) was designed and constructed. Leveraging the hypoxia tropism and phototropism exhibited by CP, we achieved targeted transport of the carrier to tumor sites. Additionally, dual near-infrared (NIR) irradiation at the tumor site facilitated photosynthesis in CP, enabling the breakdown of excessive intratumoral interstitial fluid by generating oxygen from water decomposition. This process effectively reduced the interstitial pressure, thereby promoting enhanced perfusion of blood into the tumor, significantly improving deep-seated penetration of chemotherapeutic agents, and alleviating tumor hypoxia. CONCLUSIONS: CP@ICG demonstrated a combined effect of photothermal/photodynamic/starvation therapy, exhibiting excellent in vitro/in vivo anti-tumor efficacy and favorable biocompatibility. This work provides a scientific foundation for the application of microbial-enhanced intratumoral drug delivery and tumor therapy.

Nanomedicine alleviates doxorubicin-induced cardiotoxicity and enhances chemotherapy synergistic chemodynamic therapy.

Doxorubicin (DOX) is widely used in clinic as a broad-spectrum chemotherapy drug, which can enhance the efficacy of chemodynamic therapy (CDT) by interfering tumor-related metabolize to increase H2O2 content. However, DOX can induce serious cardiomyopathy (DIC) due to its oxidative stress in cardiomyocytes. Eliminating oxidative stress would create a significant opportunity for the clinical application of DOX combined with CDT. To address this issue, we introduced sodium ascorbate (AscNa), the main reason is that AscNa can be catalyzed to produce H2O2 by the abundant Fe3+ in the tumor site, thereby enhancing CDT. While the content of Fe3+ in heart tissue is relatively low, so the oxidation of AscNa had tumor specificity. Meanwhile, due to its inherent reducing properties, AscNa could also eliminate the oxidative stress generated by DOX, preventing cardiotoxicity. Due to the differences between myocardial tissue and tumor microenvironment, a novel nanomedicine was designed. MoS2 was employed as a carrier and CDT catalyst, loaded with DOX and AscNa, coating with homologous tumor cell membrane to construct an acid-responsive nanomedicine MoS2-DOX/AscNa@M (MDA@M). In tumor cells, AscNa enhances the synergistic therapy of DOX and MoS2. In cardiomyocytes, AscNa could effectively reduce the cardiomyopathy induced by DOX. Overall, this study enhanced the clinical potential of chemotherapy synergistic CDT.

CdSe@CdS quantum dot-sensitized Au/α-Fe2O3 structure for photoelectrochemical detection of circulating tumor cells.

Circulating tumor cells (CTCs) are the important biomarker for cancer diagnosis and individualized treatment. However, due to the extreme rarity of CTCs (only 1-10 CTCs are found in every milliliter of peripheral blood) high sensitivity and selectivity are urgently needed for CTC detection. Here, a sandwich PEC cytosensor for the ultrasensitive detection of CTCs was developed using the photoactive material Au NP/-Fe2O3 and core-shell CdSe@CdS QD sensitizer. In the proposed  protocol, the CdSe@CdS QD/Au NP/α-Fe2O3-sensitized structure with cascade band-edge levels could evidently promote the photoelectric conversion efficiency due to suitable light absorption and efficient electron-hole pair recombination inhibition. Additionally, a dendritic aptamer-DNA concatemer was constructed for highly efficient capture of MCF-7 cells carrying CdSe@CdS QDs, a sensitive material. The linear range of this proposed signal-on PEC sensing method was 300 cell mL-1 to 6 × 105 cell mL-1 with a detection limit of 3 cell mL-1, and it demonstrated an ultrasensitive response to CTCs. Furthermore, this PEC sensor enabled accurate detection of  CTCs in serum samples. Hence, a promising strategy for CTC detection in clinical diagnosis was developed based on CdSe@CdS QD-sensitized Au NP/α-Fe2O3-based PEC cytosensor with dendritic aptamer-DNA concatemer.

Dual-activity nanozyme to initiate tandem catalysis for doubly enhancing ATP-depletion anti-tumor therapy.

Nanozymes can regulate metabolism to achieve precise anti-tumor therapy. However, the application of nanozymes with single catalytic properties is limited by complex tumor microenvironment (TME). Herein, we report a rarely discovered nanozyme ruthenium (Ru), which has double catalytic activity of glucose-oxidase-like (GOx-like) activity and peroxidase-like (POD-like) activity. Importantly, the GOx-like activity of Ru was proposed for the first time, which can catalyze glucose and O2 to product H2O2. And then, Ru nanozyme can connect the tandem catalysis to enhance various tumor therapy. Firstly, the atovaquone (ATO) and Ru NPs were covered with a hybrid membrane of tumor cells and liposomes to obtain Ru@ATO-Lip/M with homologous targeting. Due to the enhanced permeability and retention (EPR) effect and the tumor targeting, the Ru@ATO-Lip/M NPs could be efficiently delivered to tumor and taken up by tumor cells. Subsequently, the acidic environment of tumor activated Ru to catalyze H2O2 producing OH (Fenton-like reaction). Meanwhile, newly discovered ability of Ru catalyzed glucose and O2 to produce gluconic acid and H2O2, which provided sufficient substrates (H2O2) for continuously generating more OH. Therefore, Ru nanozyme aggravated the starvation and chemodynamic therapy (CDT). Further, ATO improved the hypoxia of the tumor microenvironment, achieving steadily synergistic anti-tumor effect. This study verified the glucose oxidase-like properties of Ru NPs for the first time, and the strategy enhanced the synergistic anti-tumor effects by CDT and starvation therapy, which provided a basis for further exploration of Ru nanozyme activity and application on antitumor.

MoS2 nanoflower-mediated enhanced intratumoral penetration and piezoelectric catalytic therapy.

The absence of lymphatic vessels in tumors leads to the retention of interstitial fluid, and the formation of an inverse pressure difference between the tumor and blood vessels hinders drug delivery deep into the tumor, which leads to tumor recurrence and metastasis. Therefore, we designed a novel strategy to downregulate tumor interstitial fluid pressure (TIFP) by water splitting in the tumor interstitium based on piezoelectric catalysis nanomedicine. First, the chemotherapeutic drug doxorubicin (DOX) was loaded on the piezoelectric catalytic material MoS2 and then encapsulated with tumor cell membrane (CM) to obtain MD@C. MD@C could not only target the tumor through homologous targeting but, more importantly, also triggered piezoelectric catalytic water splitting under ultrasound (US) stimulation; as a result, the TIFPs of U14 and PAN02 tumor-bearing mice were reduced to 57.14% and 45.5%, respectively, and the tumor inhibition rates of MD@C were 96.75% and 99.21%, which increased the perfusion of blood-derived drugs in the tumors. Moreover, the hydroxyl radicals generated by piezoelectric catalysis could effectively inhibit the growth of tumors in combination with DOX. Consequently, the piezoelectric catalytic water splitting strategy of MD@C can enhance drug delivery, providing a new universal platform for the treatment of solid malignant tumors.

Aptamer-mediated DNA concatemer functionalized magnetic nanoparticles for reversible capture and release of circulating tumor cells.

Effectively capturing, releasing, and reanalyzing circulating tumor cells (CTCs) are critical in cancer diagnosis and individualized treatment. Traditional immunomagnetic separation has disadvantages of low sensitivity and specificity, and is time-consuming and costly in CTCs capture. It is also easily disturbed by the microenvironment in releasing and analyzing CTCs. Here, we proposed an aptamer-mediated DNA concatemer functionalized magnetic nanoparticles (MNPs-AMDC) for the reversible capture and release of CTCs. In this study, aptamers were used both for efficiently capturing CTCs without complicated assembly steps and stimulus-response switch for releasing CTCs with little influence on cellular activity. The MNPs-AMDC was demonstrated to effectively capture (83%) and release CTCs with a good viability rate (92%). Moreover, this device was also tested in clinical blood samples, which would provide a universal tool for diagnosing cancer and treating individuals.

Plasmonic enhanced enzyme activity by catalytic cascade induced mutual benefit tumor starvation/immune/photothermal therapy.

Single tumor starvation therapy can activate other signaling pathways in tumor cells and easily induce tumor cell metastasis. This research proposes an intelligent nanoparticle, which is effectively combined with plasmonic and immunotherapy to realize a new strategy of "upstream consumption and downstream blocking" of nutrients in tumor sites. The intelligent nanoparticle (Ag-G/C@M) was composed of Ag NCs loaded with glucose oxidase (GOx), catalase (CAT) and coated with the tumor cytomembrane (M). Homologous targeting of tumor cytomembrane facilitated more delivery of Ag-G/C@M to tumor sites and then the plasmonic excited from Ag-G/C@M can increase the catalytic efficiency of the enzymatic reaction. Hydrogen peroxide (H2O2) produced by Ag-G/C@M through the consumption of glucose is further catalyzed by CAT to produce oxygen (O2). This self-reinforcing cascade reaction not only consumes the nutrients of tumor cells, but also the plasmonic-induced photothermal therapy can further stimulate the immune system to produce interferon-γ (IFN-γ), blocking angiogenesis and restricting the nutrient supply of tumor cells. This strategy takes the nutrition necessary for cell survival as the entry point, through endogenous continuous consumption of intracellular nutrients and containment of exogenous supplementation, combined with plasmonic thermal effect and immunotherapy to kill tumor cells, which provides a new way of treating cancer safely and effectively.

Diagnostic and therapeutic nanoenzymes for enhanced chemotherapy and photodynamic therapy.

Nanozymes, as a kind of artificial mimic enzymes, have superior catalytic capacity and stability. As lack of O2 in tumor cells can cause resistance to drugs, we designed drug delivery liposomes (MnO2-PTX/Ce6@lips) loaded with catalase-like nanozymes of manganese dioxide nanoparticles (MnO2 NPs), paclitaxel (PTX) and chlorin e6 (Ce6) to consume tumor's native H2O2 and produce O2. Based on the catalysis of MnO2 NPs, a large amount of oxygen was produced by MnO2-PTX/Ce6@lips to burst the liposomes and achieve a responsive release of the loaded drug (paclitaxel), and the released O2 relieved the chemoresistance of tumor cells and provided raw materials for photodynamic therapy. Subsequently, MnO2 NPs were decomposed into Mn2+ in an acidic tumor environment to be used as contrast agents for magnetic resonance imaging. The MnO2-PTX/Ce6@lips enhanced the efficacy of chemotherapy and photodynamic therapy (PDT) in bearing-tumor mice, even achieving complete cure. These results indicated the great potential of MnO2-PTX/Ce6@lips for the modulation of the TME and the enhancement of chemotherapy and PDT along with MRI tracing in the treatment of tumors.

Gaseous microenvironmental remodeling of tumors for enhanced photo-gas therapy and real-time tracking.

The gaseous microenvironment (GME) of tumors is rapidly becoming a new concern for nanotechnology-mediated oncotherapy. Here, we constructed a tumor/near-infrared (NIR) light-responsive nanoplatform to generate O2 and NO for remodeling the GME of tumors and phototherapy. The biocompatible and pyrolytic polydopamine was used to load indocyanine green, NONOate, and MnO2 NPs as a nanoenzyme (PINM). Then, HA was modified on the PINM to form the final nanoplatform (PINMH). PINMH can target tumors favorably due to the modification of HA. Under the NIR light irradiation, PINM converts the light and O2 to hyperpyrexia (58.5 °C) and cytotoxic 1O2. MnO2 NPs catalyze the H2O2 overexpressed in tumors to O2, which increases the amount of 1O2. Moreover, NONOate decomposes to NO (100 µM) under hyperpyrexia, thus leading to the gas therapy. The results verified that the responsive nanoplatform with precise gaseous regulation and phototherapy exhibited a superior anti-tumor effect (V/V0 = 1.2) and biosafety. In addition, PINMH can be tracked in real-time via magnetic resonance imaging. In this study, an intelligent nano-platform integrated with diagnosis and treatment was developed, which used the phototherapy technology to reshape GME and achieve good anti-tumor effects, aiming to provide an innovative and reasonable strategy for the development of tumor treatment.

A homologous-targeting "nanoconverter" with variable size for deep tumor penetration and immunotherapy.

Tumor-associated immunosuppression, as a key barrier, prevents immunotherapy-resistant tumors. In this study, an ingenious "nanoconverter" was designed to convert immunosuppression into immunoactivation, which was a C6-ceramide (C6)-modified tumor cytomembrane-coated polydopamine-paclitaxel system (PTX/PDA@M-C6). The co-administration of C6-ceramide and tumor cytomembrane changed an adaptive immune state to an activation state, which induced a robust antigen presentation ability of tumor-infiltrating dendritic cells to activate T1 helper cells and cytotoxic T lymphocytes. Meanwhile, C6-ceramide regulated the phenotype of macrophages via the reactive oxygen species pathway, which resulted in the conversion of M2-like macrophages by infiltration within tumors into M2-like macrophages, and therefore, M2-like macrophage-mediated immunosuppression was weakened distinctly. The "nanoconverter"-mediated conversion process upregulated the expression of related immune factors including interleukin-12, interleukin-6, tumor necrosis factor-α and interferon-γ and executed positive anti-tumor effects. In addition, under the protection of tumor-homologous cytomembrane, the "nanoconverter" exhibited excellent delivery efficiency (23.22%), and subsequently, accumulated special structural "nanoconverter" could break down into smaller nanoparticles for deep penetration into the tumor tissue under a NIR laser. Ultimately, chemo/thermal therapy-assisted immunotherapy completely eliminated the tumors of tumor-bearing mice, and a potent memory response relying on effector memory T cells still persisted to protect against tumor relapse after the end of treatment. The "nanoconverter" serves as a promising nanodrug delivery system for the conversion of immunosuppression and enhanced chemo/thermal therapy. Therefore, the highly cumulative "nanoconverter" has great potential for promoting the effect and clinical application of immunotherapy.