Synergistic Tumor Therapy Research Articles

Simple theranostics nanoagent for precision suppression of tumor growth and metastasis: A traditional fermented product having a novel functional breakthrough

Biomass-based nanoagents constitute a focal point in the clinical development of tumor nanotheranostics, characterized by their high biocompatibility, biodegradability, controllability, and sustainability. However, achieving satisfactory nanoagents with biological safety and high theranostic efficacy for clinical translation remains a significant challenge. Herein, based on the design concept of medicine food homology, we developed a simple, mass-produced theranostics nanoagent (HSAVMn@CM NA) using Shanxi aged vinegar (SAV) as the raw material, enabling second near-infrared fluorescence/photoacoustic (NIR-II FL/PA) imaging-guided photo/catalytic/chemodynamic synergistic tumor therapy. A novel strategy involving the hydrolysis of SAV (HSAV) via the hydrolysis-acidification method has been developed to enhance NIR-II FL imaging performance. The HSAVMn@CM NAs have improved tumor-targeted efficiency through biomimetic modification of tumor membranes. Guided by NIR-II FL/PA dual-modal imaging, the HSAVMn@CM NAs achieve targeted photothermal/photodynamic synergistic phototherapy. Notably, the employment of a single laser source for simultaneous photothermal/photodynamic therapy has led to an enhancement in the efficacy of phototherapy. Moreover, the HSAVMn@CM NAs effectively chelated Zn2+ ions within the tumor microenvironment, to inhibit matrix metalloproteinase 2/9 (MMP 2/9) activity, thereby synergistically suppressing primary tumor growth and metastasis. Taken together, this research provides a novel design strategy for biomass-based nanoagents with potential clinical translation in precise tumor theranostics.

Photothermal amplified multizyme activity for synergistic photothermal-catalytic tumor therapy

Nano-enzymatic catalytic therapy has been widely explored as a promising tumor therapeutic method with specific responsiveness to the tumor microenvironment (TME). However, the inherent lower and simplex catalytic efficiency impairs their anti-tumor efficacy. Therefore, developing novel nanozymes with relatively high and multiple catalytic characteristics, simultaneously enhancing the enzyme-like activity of nanozymes using the proper method, photothermal promoted catalytic property, is a reliable way. In this paper, we report a manganese oxide/nitrogen-doped carbon composite nanoparticles (MnO-N/C NPs) with multi-enzyme mimetic activity and photothermal conversional effect. The peroxidase (POD)-like/oxidase (OXD)-like/catalase (CAT)-like activity of MnO-N/C nanozymes was accelerated upon exposure to an 808 nm NIR laser. In vitro and in vivo results proved that the MnO-N/C NPs shown excellent magnetic resonance imaging (MRI) guided synergistic photothermal-enhanced catalytic treatment and photothermal therapy of liver cancer. The photothermal enhanced multi-enzyme activity maximizes the efficacy of catalytic and photothermal therapy while reducing harm to healthy cells, thereby offering valuable insights for the development of next-generation photothermal nanozymes to enhance tumor therapy.

Engineering small extracellular vesicles with multivalent DNA probes for precise tumor targeting and enhanced synergistic therapy

Small extracellular vesicles (sEVs) have gained wide attention as efficient carriers for disease treatment. However, the proclivity of sEVs to be ingested by source cells is insufficient to accurately target specific sites, posing a challenge in realizing controlled targeting treatment. Here, we developed an engineered sEV nanocarrier capable of precise tumor targeting and enhanced synergistic therapy. Multivalent DNA probes, comprising abundant AS1411 aptamers and telomerase primers, were innovatively modified on the sEV membrane (M-D-sEV) for precise tumor targeting. To achieve synergistic therapy, gold nanorod-cerium oxide nanostructures (Au NRs-CeO2) and manganese dioxide nanosheets-doxorubicin (MnO2 NSs-DOX) were encapsulated into liposomes (Lip-Mat). Then M-D-sEV and Lip-Mat were fused together through membrane fusion to obtain nanocarriers. Owing to the multivalence of the probes, the surface of the nanocarriers was loaded with numerous aptamers, which greatly enhances their targeting ability and promotes the accumulation of drugs. When nanocarriers were ingested by tumor cells, telomerase and multivalent DNA probes triggered their aggregation, enhancing the therapeutic effect. Furthermore, under laser irradiation, Au NRs-CeO2 converted light into hyperthermia, thereby inducing the destruction of nanocarriers membrane. This process initiated a series of reactions involving glutathione and H2O2 consumption, as well as DOX release, ultimately achieving synergistic tumor therapy. In vitro and in vivo studies demonstrated the remarkable targeting ability of multivalent DNA probes and excellent therapeutic effect of this strategy. The engineered strategy of sEVs provide a promising approach for precise tumor therapy and hold great potential for the development of efficient, safe, and personalized drug delivery systems.

Acidic Lysosome-Anchoring Croconium-Based Nanoplatform for Enhanced Triple-Mode Bioimaging and Fe3+-Triggered Tumor Synergistic Therapy.

Metal-modulated croconium dyes with multimodal-imaging and synergistic therapy in the tumor microenvironment have exhibited great potential in tumor theranostics. However, their unideal structure optimization always weakened the efficacy of near-infrared fluorescence-photoacoustic (NIRF/PA) imaging and photothermal therapy (PTT). Here, we screened croconium dye containing two indole groups with better NIRF/PA imaging and PTT in their family, linked to two morpholine rings, and obtained CR-736, as a lysosome-targeting and Fe3+-modulated agent. The established CR-736-Fe3+ nanoplatform was accurately delivered to the breast tumor site, released CR-736 and Fe3+ in the lower acidic lysosome microenvironment, and activated pH-responsive NIRF/PA/magnetic resonance imaging and PTT. Furthermore, ferroptosis generated hydroxyl free radicals and lipid peroxide by consuming GSH and H2O2 by dint of the accumulation of Fe3+ in tumor cells, which resulted in the inhibition of the expression of heat shock proteins and the concomitant recovery of PTT. The synergistic therapy of PTT, ferroptosis, and chemodynamics was further optimized to the maximal extent in tumor lysosome acidic microenvironment and proved both in vitro and a mouse tumor model. This study opens a new avenue in designing excellent and unique croconium-based nanoplatforms, synergizing multiple tumor theranostic methods, and further optimizing the theranostic effects in tumor microenvironment.

Hyaluronic acid-coated porphyrin nanoplatform with oxygen sustained supplying and glutathione depletion for enhancing photodynamic/ion/chemo synergistic cancer treatment

Hypoxia and high concentration of glutathione (GSH) in tumor seriously hinder the role of reactive oxygen species (ROS) and oxygen-dependence strategy in tumor treatment. In this work, a self-generating oxygen and self-consuming GSH hyaluronic acid (HA)-coated porphyrin nanoplatform (TAPPP@CaO2/Pt(IV)/HA) is established for enhancing photodynamic/ion/chemo targeting synergistic therapy of tumor. During the efforts of ROS production by nanosystems, a GSH consuming strategy is implemented for augmenting ROS-induced oxidative damage for synergetic cancer therapy. CaO2 in the nanosystems is decomposed into O2 and H2O2 in an acidic environment, which alleviates hypoxia and enhances the photodynamic therapy (PDT) effect. Calcium overload causes mitochondria dysfunction and induces apoptosis. Pt (IV) reacts with GSH to produce Pt (II) for chemotherapy and reduce the concentration of GSH, protecting ROS from scavenging for augmenting ROS-induced oxidative damage. In vitro and in vivo results demonstrated the self-generating oxygen and self-consuming GSH strategy can enhance ROS-dependent PDT coupled with ion/chemo synergistic therapy. The proposed strategy not only solves the long-term problem that hypoxia limits therapeutic effect of PDT, but also ameliorates the highly reducing environment of tumors. Thus the preparation of TAPPP@CaO2/Pt(IV)/HA provided a novel strategy for the effective combined therapy of cancers.

Environment-responsive dopamine nanoplatform for tumor synergistic therapy

Nanoparticle-based photothermal therapy (PTT) has emerged as a promising approach in tumor treatment due to its high selectivity and low invasiveness. However, the penetration of near-infrared light (NIR) is limited, leading it fails to induce damage to the deep-seated tumor cells within the tumor tissue. Additionally, inefficient uptake of photothermal nanoparticles by tumor cells results in suboptimal outcomes for PTT. In this study, we utilized the adhesive properties of photothermal material, polydopamine (PDA), which can successfully load the photosensitizer indocyanine green (ICG) and chemotherapeutic drug doxorubicin (DOX) to achieve photothermal and chemotherapy synergy treatment (PDA/DOX&ICG), aiming to compensate the defects of single tumor treatment. To extending the blood circulation time of PDA/DOX&ICG nanoparticles, evading clearance by the body immune system and achieving targeted delivery to tumor tissues, a protective envelopment was created using erythrocyte membranes modified with folate acid (FA-EM). After reaching the tumor tissue, the obtained FA-EM@PDA/DOX&ICG nanoparticles can specific bind with folate acid receptors on the surface of tumor cells, which can improve the uptake behavior of FA-EM@PDA/DOX&ICG nanoparticles by tumor cells, and leading to the release of loaded DOX and ICG in response to the unique tumor microenvironment. ICG, as a typical photosensitizer, significantly enhances the photothermal conversion performance of FA-EM@PDA/DOX&ICG nanoparticles, thus inducing tumor cells damage. In vitro and in vivo experimental results demonstrated that the coordinated NIR treatment with FA-EM@PDA/DOX&ICG not only effectively inhibits tumor growth, but also exhibits superior biocompatibility, effectively mitigating DOX-induced tissue damage.

Perovskite-structured ultrasensitive CaMnO3 nanoenzyme enables highly efficient ultrasound-amplified and catalysis-involved synergistic tumor therapy

Catalytic nanoenzyme-mediated therapy with reactive oxygen species generation feature and tumor microenvironment regulation characteristic has demonstrated high therapeutic efficacy in oncological field, whereas its low enzyme-mimicking reaction efficacy typically results in dissatisfied therapeutic effect and outcome. Herein, an ultrasensitive CaMnO3 (CMO) nanoenzyme has been rationally designed and engineered for enzyodynamic-calcium overload synergistic tumor therapy. CMO nanoenzyme with oxidase (OXD)-, peroxidase (POD)- and glutathione peroxidase (GPx)-mimic activities is responsible for the generation of reactive oxygen species, the consumption of intra-tumor glutathione and mitochondrial damage. For the evaluation of OXD and POD-mimicking activities, CMO with ultra low concentration (1 μg ml−1) can rapidly catalyze the color reaction of 3,3′,5,5′-tetramethylbenzidine (TMB) hydrochloride and reach the reaction termination in a very short time (1 s). Moreover, the release and overload of Ca2+ strengthen the tumor cell death. Exogenous ultrasound stimulation further amplifies the enzyodynamic-Ca2+ overload synergistic tumor-therapeutic efficacy. In vitro and in vivo results affirm the transcendent antineoplastic outcomes of CMO. Meanwhile, the existence of Mn2+ endows nanoenzyme with T1-weighted MR imaging capacity. This work provides new strategies for efficient enzyme-mimicking activity and tumor synergistic treatment based on new perspectives on the engineering of multifunctional therapeutic nanomedicine.

Copper-Induced Supramolecular Peptide Assemblies for Multi-Pathway Cell Death and Tumor Inhibition.

Although self-assembly has emerged as an effective tool for fabricating biomaterials, achieving precise control over the morphologies and functionalities of the resultant assemblies remains an ongoing challenge. Inspired by the copper peptide naturally present in human plasma, in this study, we designed a synthetic precursor, FcGH. FcGH can self-assemble via two distinct pathways: spontaneous and Cu2+-induced. These two assembly pathways enabled the formation of assemblies with tunable morphologies by adjusting the amount of added Cu2+. We found that the nanoparticles formed by Cu2+-induced self-assembly exhibited a significantly higher cellular uptake efficiency than the wormlike fibers formed spontaneously. Moreover, this Cu2+-induced assembly process occurred spontaneously at a 1 : 1 molar ratio of Cu2+ to FcGH, avoiding the excessive use of Cu2+ and a tedious preparation procedure. By co-assembling with 10-hydroxycamptothecin (HCPT)-conjugated FcGH, Cu2+-induced supramolecular nanodrugs elicited multiple cell death modalities in cancer cells with elevated immunogenicity, enhancing the therapeutic effect compared to free HCPT. This study highlights Cu2+-induced self-assembly as an efficient tool for directing the assembly of nanodrugs and for synergistic tumor therapy.

Copper‐Induced Supramolecular Peptide Assemblies for Multi‐Pathway Cell Death and Tumor Inhibition

AbstractAlthough self‐assembly has emerged as an effective tool for fabricating biomaterials, achieving precise control over the morphologies and functionalities of the resultant assemblies remains an ongoing challenge. Inspired by the copper peptide naturally present in human plasma, in this study, we designed a synthetic precursor, FcGH. FcGH can self‐assemble via two distinct pathways: spontaneous and Cu2+‐induced. These two assembly pathways enabled the formation of assemblies with tunable morphologies by adjusting the amount of added Cu2+. We found that the nanoparticles formed by Cu2+‐induced self‐assembly exhibited a significantly higher cellular uptake efficiency than the wormlike fibers formed spontaneously. Moreover, this Cu2+‐induced assembly process occurred spontaneously at a 1 : 1 molar ratio of Cu2+ to FcGH, avoiding the excessive use of Cu2+ and a tedious preparation procedure. By co‐assembling with 10‐hydroxycamptothecin (HCPT)‐conjugated FcGH, Cu2+‐induced supramolecular nanodrugs elicited multiple cell death modalities in cancer cells with elevated immunogenicity, enhancing the therapeutic effect compared to free HCPT. This study highlights Cu2+‐induced self‐assembly as an efficient tool for directing the assembly of nanodrugs and for synergistic tumor therapy.

STAT3-specific nanocarrier for shRNA/drug dual delivery and tumor synergistic therapy

Non-small cell lung cancer (NSCLC) is a major disease with high incidence, low survival rate and prone to develop drug resistance to chemotherapy. The mechanism of secondary drug resistance in NSCLC chemotherapy is very complex, and studies have shown that the abnormal activation of STAT3 (Signal Transducer and Activator of Transcription 3) plays an important role in it. In this study, the pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid was constructed with STAT3 as the precise target. By modifying hydrophilic and hydrophobic blocks onto chitosan, a multifunctional vitamin E succinate-chitosan-polyethylene glycol monomethyl ether histidine (VES-CTS-mPEG-His) micelles were synthesized. The micelles could encapsulate hydrophobic drug doxorubicin through self-assembly, and load the recombinant pGPU6/GFP/Neo STAT3-shRNA (pDNA) through positive and negative charges to form dual-loaded nanoparticles DOX/VCPH/pDNA. The co-delivery and synergistic effect of DOX and pDNA could up-regulate the expression of PTEN (Phosphatase and Tensin Homolog), down-regulate the expression of CD31, and induce apoptosis of tumor cells. The results of precision targeted therapy showed that DOX/VCPH/pDNA could significantly down-regulate the expression level of STAT3 protein, further enhancing the efficacy of chemotherapy. Through this study, precision personalized treatment of NSCLC could be effectively achieved, reversing its resistance to chemotherapy drugs, and providing new strategies for the treatment of drug-resistant NSCLC.

DNA aptamer-empowered self-assembly full-API nanodrug for enhanced photodynamic and chemotherapy synergistic cancer therapy

Nanomedicine holds promising potential for cancer therapy, yet challenges such as low active pharmaceutical ingredient (API), nanocarrier toxicity, complex preparation processes, and a lack of targeting ability hinder clinical applications. Here, we present a versatile method for preparing DNA aptamer-based full-API nanodrugs (ICS AFANDs). This approach involves the self-assembly of FDA-approved chemotherapeutics (irinotecan), photosensitive drugs (Chlorin e6, Ce6), and the DNA molecule of the Sgc8 aptamer. DNA aptamers are firstly confirmed to not only impart solubilization and targeting ability to ICS AFANDs but also play a pivotal role in engineering and stabilizing the formation of self-assembled nanodrugs. Our method not only significantly enhances the chemotherapy effectiveness of irinotecan by 102-fold, but also improves the near-infrared (NIR) fluorescence properties and photoactivity of Ce6. Combining photodynamic therapy (PDT) and chemotherapy (CT), our ICS AFANDs achieve complete suppression of colorectal cancer growth, with only one dose and one laser treatment, all without apparent side effects. Our strategy is a versatile method for preparing carrier-free and multifunctional DNA nanodrugs for synergistic tumor therapy. The smart and efficient full-API DNA nanodrug not only broadens the scope of synergistic tumor therapy but also facilitates the practical translation of DNA nanodrugs to clinical use.

Preparation of environmentally responsive PDA&DOX@LAC live drug carrier for synergistic tumor therapy

The development of intelligent, environmentally responsive and biocompatible photothermal system holds significant importance for the photothermal combined therapy of tumors. In this study, inspired by Lactobacillus (LAC), we prepared a biomimetic nanoplatform PDA&DOX@LAC for tumor photothermal-chemotherapy by integrating the chemotherapeutic drug doxorubicin (DOX) with dopamine through oxidative polymerization to form polydopamine (PDA) on the surface of LAC. The PDA&DOX@LAC nanoplatform not only achieves precise and controlled release of DOX based on the slightly acidic microenvironment of tumor tissues, but also exhibits enzyme-like properties to alleviate tumor hypoxia. Under near-infrared light irradiation, it effectively induces photothermal ablation of tumor cells, enhances cellular uptake of DOX with increasing temperature, and thus efficiently inhibits tumor cell growth. Moreover, it is further confirmed in vivo experiments that photothermal therapy combined with PDA&DOX@LAC induces tumor cells apoptosis, releases tumor-associated antigens, which is engulfed by dendritic cells to activate cytotoxic T lymphocytes, thereby effectively suppressing tumor growth and prolonging the survival period of 4T1 tumor-bearing mice. Therefore, the PDA&DOX@LAC nanoplatform holds immense potential in precise tumor targeting as well as photothermal combined therapy and provides valuable insights and theoretical foundations for the development of novel tumor treatment strategies based on endogenous substances within the body.

An intelligent Cu/ZIF-8-based nanodrug delivery system for tumor-specific and synergistic therapy via tumor microenvironment-responsive cascade reaction.

Anintelligent nanodrug delivery system (Cu/ZIF-8@GOx-DOX@HA, hereafter CZGDH) consisting of Cu-doped zeolite imidazolate framework-8 (Cu/ZIF-8, hereafter CZ), glucose oxidase (GOx), doxorubicin (DOX), and hyaluronic acid (HA) was established for targeted drug delivery and synergistic therapy of tumors. The CZGDH specifically entered tumor cells through the targeting effect of HA and exhibited acidity-triggered biodegradation for subsequent release of GOx, DOX, and Cu2+ in thetumor microenvironment (TME). The GOx oxidized the glucose (Glu) in tumor cells to produce H2O2 and gluconic acid for starvation therapy (ST). The DOX entered the intratumoral cell nucleus for chemotherapy (CT). The released Cu2+ consumed the overexpressed glutathione (GSH) in tumor cells to produce Cu+. The generated Cu+ and H2O2 triggered the Fenton-like reaction to generate toxic hydroxyl radicals (·OH), which disrupted the redox balance of tumor cells and effectively killed tumor cells for chemodynamic therapy (CDT). Therefore, synergistic multimodal tumor treatment via TME-activated cascade reaction was achieved. The nanodrug delivery system has a high drug loading rate (48.3wt%), and the three-mode synergistic therapy has a strong killing effect on tumor cells (67.45%).

Homologous Tumor Targeting Molybdenum‐Doped Prussian Blue for Enhancing Immunotherapy via PTT/CDT and Remodeled Tumor Immune Microenvironment

AbstractImmunotherapy offers a promising avenue for reducing tumor metastasis and recurrence but faces challenges from the tumor immunosuppressive microenvironment (TIME) and restricted antigen presentation. To address these challenges, this study have developed an innovative approach utilizing molybdenum (Mo)‐doped Prussian blue nanoparticles coated with a cancer cell membrane (CCM), referred to as PMo@CCM. This novel nanoplatform excels in performing photothermal therapy (PTT), while the Mo and Fe components effectively deplete glutathione (GSH) and generate reactive oxygen species (ROS), thereby significantly enhancing chemodynamic therapy (CDT) and remodeling the TIME. The synergistic PTT/CDT approach not only induces tumor immunogenic cell death (ICD) but also facilitates antigen presentation. The CCM coating further supplies antigens and prompts dendritic cell (DC) maturation. This comprehensive strategy markedly enhances the effectiveness of immunotherapy, as evidenced by a significant increase in T cell activation. Moreover, the use of programmed cell death protein 1 antibodies (anti PD‐1) effectively blocks the PD‐1 immune checkpoint pathway. RNA sequencing analysis has identified genes associated with the observed substantial reduction in tumor growth. In conclusion, the PMo@CCM nanoplatform enables homologously targeted tumor synergistic therapy, guided by photothermal and magnetic resonance imaging (PTI&MRI), significantly impeding the progression of both primary and metastatic tumors.

Drug delivery particles for targeted imaging-guided photothermal/chemotherapy synergy cancer therapy

The early stage of pancreatic cancer is asymptomatic and the treatment effect is not ideal. The progression to the advanced stage leads to a close relationship between mortality and morbidity. Therefore, there is an urgent need to develop precise and efficient therapeutic strategies to combat pancreatic cancer. In this study, we introduce a near-infrared (NIR) targeted drug delivery nanoparticle for ultrasound (US) imaging to guide magnetothermal/chemotherapy synergistic treatment of pancreatic cancer. Carboxylated polylactic acid (PLGA-PEG-COOH) serves as the structure of the nanoparticles, specifically binding the RGD cyclic peptide for pancreatic cancer targeting activity and promoting tumor aggregation of the nanoparticles. NIR-induced superparamagnetic iron oxide (SPIO) nanoparticles convert near-infrared light into thermal energy, triggering vaporization of perfluoropentane (PFH) droplets to generate PFH bubbles that enhance US imaging and help load doxorubicin (DOX), which are released from nanoparticles. SPIO can also be used for thermal ablation of tumors to improve therapeutic effect in treating pancreatic cancer. The results show that the targeted particles mediated by NIR have the characteristics of targeted drug delivery imaging. The microspheres exhibit strong acoustic and near-infrared responsiveness. Cell proliferation experiments showed that IR-mediated PFH-DOX@PLGA/SPIO-RGD NPs (RNPs) had a higher inhibitory effect on cell proliferation. Animal experiments have shown that RNPS can accumulate highly in the tumor area and show good therapeutic effect. In conclusion, this nanotherapeutic particle is a very promising targeted image-guided photothermal/chemotherapeutic synergistic tumor therapy strategy.

3D‐Printed Tissue‐Specific Nanospike‐Based Adhesive Materials for Time‐Regulated Synergistic Tumor Therapy and Tissue Regeneration In Vivo

AbstractThe growing concerns regarding cancer recurrence, unpredictable bone deficiencies, and postoperative bacterial infections subsequent to the surgical removal of bone tumors have highlighted the need for multifaceted bone scaffolds that afford tumor therapy, bacterial therapy, and effective vascularized bone reconstruction. However, challenging trilemma has emerged in the realm of bone scaffolds regarding the balance between achieving appropriate mechanical strength, ensuring biocompatibility, and optimizing a degradation rate that aligns with bone‐regenerative rate. Considering these challenges, innovative theragenerative platform is developed by utilizing 3D printing‐based nanospikes for the first time. This platform comprises tissue‐specific nanospiked hydroxyapatite decorated with magnesium (nMg) and adhesive DNA (aDNA). The incorporation of nMg within polylactic acid (PLA) matrix confers photothermal capabilities and helps to modulate mechanical and degradation properties and improve the biocompatibility of theragenerative platform. Simultaneously, the immobilized aDNA contributed to the enhancement of vascularized bone healing. These 3D‐printed tissue‐adhesive theragenerative platforms exhibit superior mechanical properties and offer controlled degradability. Moreover, they enable the eradication of bacteria and osteosarcoma through hyperthermia and promote angiogenesis and osteogenesis, both in vitro and in vivo. This groundbreaking approach is poised to pave the way for the fabrication and design of novel implantable biomaterials that integrate therapeutic and regenerative functions.

Manganese-induced Photothermal-Ferroptosis for Synergistic Tumor Therapy

Ferroptosis-related tumor therapy based on nanomedicines has recently gained significant attention. However, the therapeutic performance is still hindered by the tumor's physical barriers such as the fibrotic tumor matrix and elevated interstitial fluid pressure, as well as chemical barriers like glutathione (GSH) overabundance. These physicochemical barriers impede the bioavailability of nanomedicines and compromise the therapeutic efficacy of lipid reactive oxygen species (ROS). Thus, this study pioneers a manganese-mediated overcoming of physicochemical barriers in the tumor microenvironment using organosilica-based nanomedicine (MMONs), which bolsters the synergy of photothermal-ferroptosis treatment. The MMONs display commendable proficiency in overcoming tumor physical barriers, due to their MnO2-mediated shape-morphing and softness-transformation ability, which facilitates augmented cellular internalization, enhanced tumor accumulation, and superior drug penetration. Also, the MMONs possess excellent capability in chemical barrier overcoming, including MnO2-mediated dual GSH clearance and enhanced ROS generation, which facilitates ferroptosis and heat shock protein inhibition. Notably, the resulting integration of physical and chemical barrier overcoming leads to amplified photothermal-ferroptosis synergistic tumor therapy both in vitro and in vivo. Accordingly, the comparative proteomic analysis has identified promoted ferroptosis with a transient inhibitory response observed in the mitochondria. This research aims to improve treatment strategies to better fight the complex defenses of tumors.

Oxygen Vacancy Piezoelectric Nanosheets Constructed by a Photoetching Strategy for Ultrasound "Unlocked" Tumor Synergistic Therapy.

Piezoelectric dynamic therapy (PzDT) is an effective method of tumor treatment by using piezoelectric polarization to generate reactive oxygen species. In this paper, two-dimensional Cu-doped BiOCl nanosheets with surface vacancies are produced by the photoetching strategy. Under ultrasound, a built-in electric field is generated to promote the electron and hole separation. The separated carriers achieve O2 reduction and GSH oxidation, inducing oxidative stress. The bandgap of BiOCl is narrowed by introducing surface oxygen vacancies, which act as charge traps and facilitate the electron and hole separation. Meanwhile, Cu doping induces chemodynamic therapy and depletes GSH via the transformation from Cu(II) to Cu(I). Both in vivo and in vitro results confirmed that oxidative stress can be enhanced by exogenous ultrasound stimulation, which can cause severe damage to tumor cells. This work emphasizes the efficient strategy of doping engineering and defect engineering for US-activated PzDT under exogenous stimulation.

A pH-responsive single-atom nanozyme for photothermal-augmented nanocatalytic tumor therapy

Based on the physiological conditions of the tumor microenvironment (TME), many effective therapeutic strategies have been reported by using nanocatalysts. The main challenge is the insufficient catalytic activity of nanocatalysts within the acidic TME, significantly constraining their therapeutic efficacy. Herein, a pH-responsive bifunctional platform is developed with multiple enzyme-like catalytic activities for synergistic tumor therapy by integrating Rh single atoms nanozymes (SA-Rh nanozymes) with photothermal therapy (PTT). The SA-Rh nanozymes display peroxidase-mimicking activities within tumor cells, inducing a synergistic effect of enhanced reactive oxygen species generation for collaborative cancer therapy involving both chemodynamic therapy and PTT. Additionally, SA-Rh nanozymes exhibit catalase mimicking activities, enabling the generation of oxygen, and facilitating efficient nanozyme catalytic therapy in a substrate-cycle manner. Moreover, the catalytic efficiency of SA-Rh nanozymes is found to be higher under weak acidic conditions (pH=6.0) compared to neutral conditions (pH=7.4), thereby enabling the maintenance of catalytic activity in an acidic environment. The incorporation of this feature enhances its catalytic activity within the TME, optimizing the efficacy of nanozyme. The remarkable near-infrared I region absorption capability confers SA-Rh nanozymes with exceptional PTT performance, achieving an impressive efficiency of 34.1 %. Therefore, the SA-Rh nanozymes exhibit a remarkable ability to induce apoptosis in cancer cells through synergistic CDT and PTT modalities, effectively overcoming the shortcomings of current nanozyme catalytic therapy.

PdCu nanoparticles with multienzymatic activity to treat tumors through the synergistic photothermal and chemodynamic therapy

Combined chemodynamic/photothermal therapy has great potential in tumor treatment. However, the presence of excessive glutathione (GSH) in the tumor microenvironment (TME) can attenuate its therapeutic effect, and other components in the TME have not been fully utilized as well. In this article, we designed a noble metal nanozyme called PdCu@BSA, which can be used for the combined chemodynamic therapy (CDT) and photothermal therapy (PTT) of tumor. In detail, PdCu@BSA has three different types of enzyme-like activities. Its catalase (CAT)-like activity can degrade extra H2O2 in the TME to create O2 and relieve the hypoxic situation. The glutathione oxidase (GSHox)-like activity can consume high level of GSH in the TME to reduce the consumption of reactive oxygen species (ROS). Peroxidase (POD)-like activity catalyzes H2O2 to form strong oxidized ·OH. The above enzyme-like activities enhance the effectiveness of CDT. Besides, PdCu@BSA has good photothermal effect and can be used for PTT when exposed to 1064 nm laser. Therefore, based on multiple enzyme-like activities and photothermal effects, PdCu@BSA can be employed for synergistic tumor therapy, resulting in good therapeutic outcome.