Effective Tumor Therapy Research Articles

Mitochondria‐Targeted Photoredox Catalysis Activates Pyroptosis for Effective Tumor Therapy

AbstractThe development of biocompatible and efficient photocatalytic redox systems to mimic bio‐photoreactors in living cells holds great potential for manipulating intracellular biochemical reaction processes and thus advancing tumor therapy. In this study, a mitochondria‐targeted photoredox catalyst, 2D vacancy‐rich molybdenum oxide nanosheets (Mt‐VR‐MoO3) is presented. These nanosheets possess a high density of oxygen vacancies (19.2%) and exhibit strong photocatalytic redox activity under near‐infrared (NIR) light. Following a two‐step functionalization, Mt‐VR‐MoO3 effectively disrupts mitochondrial electron flow in an oxygen‐independent manner upon irradiation with second near‐infrared (NIR‐II) light. This targeted disruption leads to on‐demand induction of substantial damage to tumor cell mitochondria, characterized by increased production of mitochondrial reactive oxygen species (mtROS) and the release of cytochrome c (Cyt c), which collectively trigger the pyroptosis of cancer cells. The approach achieved tumor‐targeted photocatalytic eradication with high efficacy (tumor growth inhibition rate of 86.9%) in an orthotopic breast 4T1 murine tumor model, with no observable harm to normal organs. These findings provide inspiration for manipulating intracellular biochemical reactions using artificial photocatalytic materials, paving the way for pyroptosis activation as a promising approach in tumor therapy.

Dual-targeted and esterase-responsive cyclodextrin-based host-guest nanocomposites for enhanced antitumor therapy

Conventional chemotherapy drugs are difficult to effectively target tumor tissue, leading to poor treatment outcomes and side effects. Actively targeted and stimuli-responsive nanomedicine greatly improves this situation, allowing for more precise drug accumulation at tumor sites. Herein, carboxymethyl-β-cyclodextrin (CMCD) - based host-guest nanocomposites (NPs) encapsulating hydroxycamptothecin (HCPT) were fabricated, which responded to esterase and had the function of targeting CD 44 receptors and the nucleus. PS-CMCD was firstly synthesized through an amide reaction of protamine (PS) and CMCD to enhance the function of penetrating membrane and nuclear localization. PS-CMCD/HCPT/HA NPs were then prepared by the host-guest complexation of PS-CMCD and HCPT and followed by surface modification of hyaluronic acid (HA) with CD44 receptor-targeting properties. The successful inclusion was also validated through computer simulation. The obtained nanocomposites displayed the esterase-responsive release behaviors of HCPT. Moreover, the synthesized PS-CMCD/HCPT/HA NPs enhanced the intracellular drug uptake due to the tumor cell- and nuclear-mediated targeting. In addition, in vivo application exhibited that PS-CMCD/HCPT/HA NPs realized good antitumor effects. These findings suggested its potential for targeted delivery and more effective tumor therapy.

Multifunctional hyaluronic acid ligand-assisted construction of CD44- and mitochondria-targeted self-assembled upconversion nanoparticles for enhanced photodynamic therapy.

Upconversion nanoparticles (UCNPs) have been used as a potential nanocarrier for photosensitizers (PSs), which have demonstrated a great deal of promise in achieving an effective photodynamic therapy (PDT) for deep-seated tumors. However, overcoming biological barriers to achieve mitochondria-targeted PDT remains a major challenge. Herein, CD44- and mitochondria-targeted photodynamic nanosystems were fabricated through the self-assembly of hyaluronic acid-conjugated-methoxy poly(ethylene glycol)-diethylenetriamine-grafted-(chlorin e6-dihydrolipoic acid-(3-carboxypropyl)triphenylphosphine bromide) polymeric ligands (HA-c-mPEG-Deta-g-(Ce6-DHLA-TPP)) and NaErF4:Tm@NaYF4 core-shell UCNPs (termed CMPNs). The CMPNs presented ideal physiological stability, a good drug loading capacity and an improved capacity for the generation of singlet oxygen (1O2) based on the FRET mechanism. Significantly, confocal images revealed that CMPNs not only facilitated cellular uptake through CD44-receptor-targeted endocytosis, subsequently enabling rapid evasion from endo-lysosomal sequestration, but also specifically targeted mitochondria, ultimately inducing a profound disruption of mitochondrial membrane potential, which triggered apoptosis upon laser irradiation, thereby significantly enhancing the therapeutic effect. Furthermore, in vitro antitumor experiments further confirmed the substantial enhancement in cancer cell killing efficiency achieved by treating with CMPNs upon near-infrared (NIR) laser irradiation. This innovative approach holds promise for the development of NIR-laser-activated photodynamic nanoagents specifically designed for mitochondria-targeted PDT, thus addressing the limitations of the current PDT treatments.

Stable Alkyne‐Bridged Conjugated Polymer Nanoparticles With a High NIR‐II Photothermal Conversion Efficiency of 71% for Effective Photothermal Tumor Therapy

AbstractOrganic photothermal materials (PTMs) in the near‐infrared (NIR) range (1000–1700 nm) are more favorable for photothermal therapy (PTT) therapeutic applications because of their greater depth of tissue penetration and better biosafety. However, the photothermal conversion efficiency (PCE) of the few NIR‐II‐responsive organic PTMs that have been investigated is still slightly low. Here, a stable alkyne‐bridged conjugated polymer, BBT‐BTE, are explored with a high PCE for tumor ablation within the NIR‐II window. The BBT‐BTE synthesized by the Stille coupling reaction has strong NIR‐II absorption, and their nanoparticles (NPs) achieved a 71% PCE under 1064 nm laser excitation, with good photothermal stability. BBT‐BTE NPs are shown to be effective in completely ablating tumors without any recurrence in both in vitro and in vivo experiments. Additionally, the biosafety of these NPs is further proven by biochemical analysis and tissue biopsy. This study developed a high‐performance NIR‐II PTM and offered practical and feasible insights into the design of efficient photothermal materials specifically for the NIR‐II window.

Tumor Metabolism Aiming Cu2-xS Nanoagents Mediate Photothermal-Derived Cuproptosis and Immune Activation.

Cuproptosis is an emerging form of cell death that relies on the targeted delivery of copper ions to lipoylated tricarboxylic acid cycle proteins. However, a major challenge associated with cuproptosis is its potential to kill both normal and tumor cells without discrimination. Therefore, it is crucial to develop strategies for precise intracellular delivery and redox control of copper to create effective cuproptosis-based tumor therapies. We have introduced a class of nanoagents called metabolism aiming Cu2-xS (MACuS) through a glucose-mediated biomineralization approach. MACuS nanoagents can be specifically targeted to tumors via the glucose transport receptor 1, and we found that NIR-II irradiation can not only result in direct hyperthermia ablation of tumor cells but also facilitate efficient cuproptosis and enhance reactive oxygen species-induced cytotoxicity in tumor cells. As a result, the triple effect of MACuS treatment induced immunogenic cell death, which triggered systemic antitumor immune responses and demonstrated potent efficacy in inhibiting growth, metastasis, and recurrence in mouse and rabbit breast cancer models. The precise intracellular delivery and redox control of copper provided by MACuS hold great potential for the development of highly efficient cuproptosis-based tumor therapies with minimal off-target effects.

Radioembolization of HCC and secondary hepatic tumors: a comprehensive review.

Transarterial radioembolization (TARE), also called Selective Internal Radiation Therapy (SIRT), has emerged as an effective locoregional therapy for primary and secondary hepatic tumors, utilizing yttrium-90 (Y90) microspheres and other agents such as holmium-166 and rhenium-188. TARE has various applications in the management of HCC across different BCLC stages. Radiation segmentectomy, which involves administering high doses of Y90 (>190 Gy), can be both curative and ablative, achieving complete necrosis of the tumor. In contrast, radiation lobectomy involves administering a lower dose of Y90 (80-120 Gy) as a neoadjuvant treatment modality to improve local control and induce future liver remnant (FLR) hypertrophy in patients who are planned to undergo surgery but have insufficient FLR. Modified radiation lobectomy combines both techniques and offers several advantages over portal vein embolization (PVE). Y90 is also used in downstaging HCC patients outside liver transplantation criteria, as well as bridging those awaiting liver transplantation (LT). Multiple studies and combined analyses were described to highlight the outcomes of TARE and compare it with other treatment modalities, including TACE and sorafenib. Additionally, the review delves into the efficacy and safety of radioembolization in managing metastatic colorectal cancer and other metastatic tumors to the liver. Recent studies have emphasized the role of personalized dosimetry for improved outcomes, and thus we described the different methods used for this purpose. Pretherapy imaging, estimating lung shunt, selection of therapeutic radionuclides, adverse effects, and cost-effectiveness were all discussed as well.

Intraparticle Electron Transfer for Long-Lasting Tumor Chemodynamic Therapy.

Chemodynamic therapy (CDT) is a novel tumor treatment method by using hydroxyl radicals (•OH) to kill cancer cells. However, its therapeutic effects are strictly confined by the short lifespan of •OH and reduced •OH generation speed. Herein, an effective CDT is achieved by both improving •OH lifetime and long-lasting generating •OH through intraparticle electron transfer within heterogeneous nanoparticles (NPs). These heterogeneous NPs are composed of evenly distributed Cu and Fe3O4 (CFO NPs) with large interaction interfaces, and electrons tend to transfer from Cu to Fe3O4 for the appearance of ≡Cu2+ and increase in ≡Fe2+. The generated ≡Cu2+ can interact with GSH, which prolongs the lifespan of •OH, produces ≡Cu+ for higher speed •OH generation with H2O2, and induces cell ferroptosis for tumor therapy. The improved ≡Fe2+ can also improve the •OH release under H2O2 until Cu is depleted. As a result, a sustainable •OH generation is achieved to promote cell apoptosis for effective tumor therapy. Since H2O2 and GSH are only overexpressed at tumor, and CFO NPs can degrade in the tumor microenvironment, these NPs are with high biosafety and can be metabolized by urine. This work provides a novel biomaterial for effective cancer CDT through intraparticle electron transfer.

Regenerating Chemotherapeutics through Copper-Based Nanomedicine: Disrupting Protein Homeostasis for Enhanced Tumor Therapy.

The bis-(diethyldithiocarbamate)-copper (CuET), the disulfiram (DSF)-Cu complex, has exhibited noteworthy anti-tumor property. However, its efficacy is compromised due to the inadequate oxidative conditions and the limitation of bioavailable copper. Because CuET can inactivate valosin-containing protein (VCP), a bioinformatic pan-cancer analysis of VCP is first conducted in this study to identify CuET as a promising anticancer drug for diverse cancer types. Then, based on the drug action mechanism, a nanocomposite of CuET and copper oxide (CuO) is designed and fabricated utilizing bovine serum albumin (BSA) as the template (denoted as CuET-CuO@BSA, CCB). CCB manifests peroxidase (POD)-mimicking activity to oxidize the tumor endogenous H2O2 to generate reactive oxygen species (ROS), enhancing the chemotherapy effect of CuET. Furthermore, the cupric ions released after enzymatic reaction can regenerate CuET, which markedly perturbs intracellular protein homeostasis and induces apoptosis of tumor cells. Meanwhile, CCB triggers cuproptosis by inducing the aggregation of lipoylated proteins. The multifaceted action of CCB effectively inhibits tumor progression. Therefore, this study presents an innovative CuET therapeutic strategy that creates an oxidative microenvironment in situ and simultaneously self-supply copper source for CuET regeneration through the combination of CuO nanozyme with CuET, which holds promise for application of CuET for effective tumor therapy.

Bacterial outer membrane vesicle nanorobot

Autonomous nanorobots represent an advanced tool for precision therapy to improve therapeutic efficacy. However, current nanorobotic designs primarily rely on inorganic materials with compromised biocompatibility and limited biological functions. Here, we introduce enzyme-powered bacterial outer membrane vesicle (OMV) nanorobots. The immobilized urease on the OMV membrane catalyzes the decomposition of bioavailable urea, generating effective propulsion for nanorobots. This OMV nanorobot preserves the unique features of OMVs, including intrinsic biocompatibility, immunogenicity, versatile surface bioengineering for desired biofunctionalities, capability of cargo loading and protection. We present OMV-based nanorobots designed for effective tumor therapy by leveraging the membrane properties of OMVs. These involve surface bioengineering of robotic body with cell-penetrating peptide for tumor targeting and penetration, which is further enhanced by active propulsion of nanorobots. Additionally, OMV nanorobots can effectively safeguard the loaded gene silencing tool, small interfering RNA (siRNA), from enzymatic degradation. Through systematic in vitro and in vivo studies using a rodent model, we demonstrate that these OMV nanorobots substantially enhanced siRNA delivery and immune stimulation, resulting in the utmost effectiveness in tumor suppression when juxtaposed with static groups, particularly evident in the orthotopic bladder tumor model. This OMV nanorobot opens an inspiring avenue to design advanced medical robots with expanded versatility and adaptability, broadening their operation scope in practical biomedical domains.

Hierarchical mesoporous silicon and albumin composite microparticles delivering DOX and FU for liver cancer treatment

Drug delivery systems based on hydrogel microcarriers have shown enormous achievements in tumor treatment. Current research direction mainly concentrated on the improvement of the structure and function of the microcarriers to effectively deliver drugs for enhanced cancer treatment with decreased general toxicity. Herein, we put forward novel hierarchical mesoporous silicon nanoparticles (MSNs) and bovine serum albumin (BSA) composite microparticles (MPMSNs@DOX/FU) delivering doxorubicin (DOX) and 5-fluorouracil (FU) for effective tumor therapy with good safety. The DOX and FU could be efficiently loaded in the MSNs, which were further encapsulated into methacrylate BSA (BSAMA) microparticles by applying a microfluidic technique. When transported to the tumor area, DOX and FU will be persistently released from the MPMSNs@DOX/FU and kept locally to lessen general toxicity. Based on these advantages, MPMSNs@DOX/FU could observably kill liver cancer cells in vitro, and evidently suppress the tumor development of liver cancer nude mice model in vivo. These results suggest that such hierarchical hydrogel microparticles are perfect candidates for liver cancer treatment, holding promising expectations for impactful cancer therapy.

Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.

EWSR1::WT1 is essential for desmoplastic small round cell tumors and upregulates the cyclin D-CDK4/6-RB axis that can be targeted with palbociclib, providing a targeted therapeutic strategy for treating this deadly tumor type.

DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy.

DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

Abstract 49: LYL119, an investigational ROR1-targeted CAR T-cell product incorporating four novel reprogramming technologies designed for effective cell therapy for solid tumors

Abstract Effective solid tumor cell therapy requires new strategies to improve T-cell activation, persistence, and durable function. We developed four complementary T-cell reprogramming technologies to enhance chimeric antigen receptor (CAR) T-cell therapy in solid tumors: 1) overexpression of the activator protein 1 (AP-1) family transcription factor c-Jun to delay T-cell exhaustion and improve antitumor activity; 2) nuclear receptor subfamily 4A member 3 (NR4A3) gene knockout (KO) to further delay exhaustion and enhance functionality; 3) Epi-RTM manufacturing protocols to preserve stem-like characteristics; and 4) Stim-RTM technology, a novel activating reagent to improve product potency compared with standard reagents. LYL119 is an investigational ROR1-targeted CAR T-cell product that combines these technologies to create potent and durable CAR T cells. Healthy or NSCLC patient donor T cells were manufactured with the Epi-R protocols, activated with Stim-R or a standard reagent, and transduced with a vector encoding a ROR1 CAR and c-Jun. The NR4A3 gene or a control gene was edited using SpyFiTM Cas9 nuclease (Aldevron®). Cytotoxicity, cytokine production, phenotype, and single-cell transcriptomic and epigenetic profiles were evaluated in vitro after antigen restimulation assays designed to promote exhaustion. CAR T cell activity was evaluated in vivo using a ROR1+ NSCLC xenograft mouse model. Research and clinical scale LYL119 products achieved ~90% genome editing efficiency at the NR4A3 target gene resulting in a 13-fold protein reduction compared to non-edited CAR T cells. LYL119 exhibited superior cytotoxicity and cytokine production upon antigen restimulation across 7 different ROR1+ solid tumor cell lines compared to CAR T cells that lacked one or more reprogramming technologies. After repeated rounds of tumor cell killing, LYL119 displayed reduced surface expression of exhaustion-related receptors (e.g. TIM-3) and higher expression of stemness-related markers (e.g. CD127) compared to non-edited CAR T cells. Furthermore, transcriptomic analysis revealed global downregulation of exhaustion-related gene signatures and retention of unique cell subsets characterized by upregulation of memory and effector-associated gene signatures. LYL119 exhibited robust antitumor efficacy in vivo across a 10-fold dose range, including a very low dose of 1 × 105 CAR T cells. Lastly, LYL119 derived from NSCLC patient donor T cells also demonstrated enhanced cytotoxicity in vitro compared to control CAR T cells. These nonclinical data suggest LYL119, which combines c-Jun overexpression, NR4A3 KO, Epi-R protocols, and Stim-R technology, can limit exhaustion, maintain stem-like features, and has the potential to provide effective and durable CAR T-cell antitumor activity in patients with ROR1+ solid tumors. Citation Format: Viola C. Lam, Aileen Li, Meritxell Galindo Casas, Jessica Barragan, Christina Cheung, Jessica Briones, Esha Afreen, Grant Vavra, Jia Lu, Purnima Sundar, Rowena Martinez, Candace Sims, Shobha Potluri, Omar Ali, Alexander S. Cheung, Rachel C. Lynn. LYL119, an investigational ROR1-targeted CAR T-cell product incorporating four novel reprogramming technologies designed for effective cell therapy for solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 49.

AS1411 aptamer/RGD dual functionalized theranostic chitosan-PLGA nanoparticles for brain cancer treatment and imaging

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies.

Orchestrating Precision within the Tumor Microenvironment by Biomimetic Nanoprodrugs for Effective Tumor Therapy.

Malignant tumors are still one of the most deadly diseases that threaten human life and health. However, developing new drugs is challenging due to lengthy trials, funding constraints, and regulatory approval procedures. Consequently, researchers have devoted themselves to transforming some clinically approved old drugs into antitumor drugs with certain active ingredients, which have become an attractive alternative. Disulfiram (DSF), an antialcohol medication, can rapidly metabolize in the physiological environment into diethyldithiocarbamate (DTC) which can readily react with Cu2+ ions in situ to form the highly toxic bis(N,N-diethyldithiocarbamate)-copper(II) (CuET) complex. In this study, DSF is loaded into mesoporous dopamine nanocarriers and surface-chelated with tannin and Cu2+ to construct M-MDTC nanoprodrugs under the camouflage of K7 tumor cell membranes. After intravenous injection, M-MDTC nanoprodrugs successfully reach the tumor sites with the help of mediated cell membranes. Under slightly acidic pH and photothermal stimulation conditions, DSF and Cu2+ are simultaneously released, forming a highly toxic CuET to kill tumor cells in situ. The generated CuET can also induce immunogenic cell death of tumor cells, increase the proportion of CD86+ CD80+ cells, and promote dendritic cell maturation. In vitro and in vivo studies of M-MDTC nanoprodrugs have shown excellent tumor-cell-killing ability and solid tumor suppression. This approach enables in situ amplification of chemotherapy in the tumor microenvironment, achieving an effective antitumor treatment.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Enhancing tumor photodynamic synergistic therapy efficacy through generation of carbon radicals by Prussian blue nanomedicine.

Significant progress has been achieved in tumor therapies utilizing nano-enzymes which could convert hydrogen peroxide into reactive oxygen species (ROS). However, the ROS generated by these enzymes possess a short half-life and exhibit limited diffusion within cells, making it challenging to inflict substantial damage on major organelles for effective tumor therapy. Therefore, it becomes crucial to develop a novel nanoplatform that could extend radicals half-life. Artesunate (ATS) is a Fe (II)-dependent drug, while the limited availability of iron (II), coupled with the poor aqueous solubility of ATS, limits its application. Here, Prussian blue (PB) was selected as a nano-carrier to release Fe (II), thus constructing a hollow Prussian blue/artesunate/methylene blue (HPB/ATS/MB) nanoplatform. HPB degraded and released iron(III), ATS and MB, under the combined effects of NIR irradiation and the unique tumor microenvironment. Moreover, Fe (III) exploited GSH to formation of Fe (II), disturbing the redox homeostasis of tumor cells and Fe (II) reacted with H2O2 and ATS to generate carbon radicals with a long half-life in situ. Furthermore, MB generates 1O2 under laser irradiation conditions. In vitro and in vivo experiments have demonstrated that the HPB/ATS/MB NPs exhibit a synergistic therapeutic effect through photothermal therapy, photodynamic therapy and radical therapy.

Bacteria-based cascade in situ near-infrared nano-optogenetically induced photothermal tumor therapy.

Rationale: Optogenetically engineered facultative anaerobic bacteria exhibit a favorable tendency to colonize at solid tumor sites and spatiotemporally-programmable therapeutics release abilities, attracting extensive attention in precision tumor therapy. However, their therapeutic efficacy is moderate. Conventional photothermal agents with high tumor ablation capabilities exhibit low tumor targeting efficiency, resulting in significant off-target side effects. The combination of optogenetics and photothermal therapy may offer both tumor-targeting and excellent tumor-elimination capabilities, which unfortunately has rarely been investigated. Herein, we construct a bacteria-based cascade near-infrared optogentical-photothermal system (EcNαHL-UCNPs) for enhanced tumor therapy. Methods: EcNαHL-UCNPs consists of an optogenetically engineered Escherichia coli Nissle 1917 (EcN) conjugated with lanthanide-doped upconversion nanoparticles (UCNPs), which are capable of locally secreting α-hemolysin (αHL), a pore-forming protein, in responsive to NIR irradiation. Anti-tumor effects of EcNαHL-UCNPs were determined in both H22 and 4T1 tumors. Results: The αHL not only eliminates tumor cells, but more importantly disrupts endothelium to form thrombosis as an in situ photothermal agent in tumors. The in situ formed thrombosis significantly potentiates the photothermic ablation of H22 tumors upon subsequent NIR light irradiation. Besides, αHL secreted by EcNαHL-UCNPs under NIR light irradiation not only inhibits 4T1 tumor growth, but also suppresses metastasis of 4T1 tumor via inducing the immune response. Conclusion: Our studies highlight bacteria-based cascade optogenetical-photothermal system for precise and effective tumor therapy.

Matrine induces ferroptosis in cervical cancer through activation of piezo1 channel.

Cervical cancer, which is a significant public health concern in women, currently lacks effective therapeutic drugs. Matrine, a constituent of the traditional Chinese herb Sophora flavescentis Radix, is known for its anti-cervical cancer properties and ability to induce programmed cell death. The induction of cancer cell ferroptosis, which is a novel cell death pattern, can become an effective clinical therapy for tumor in the future. However, the effect of matrine on ferroptosis in cervical cancer remains to be elucidated. In this study, we investigated whether matrine induces ferroptosis in cervical cancer and elucidated the underlying mechanisms. We established an SiHa-derived tumor-bearing mouse model using CB17 severe combined immunodeficient (SCID) mice and administered a group of matrine (25, 50, and 75mg/kg) and cisplatin (2mg/kg). We meticulously tracked alterations in body weight and tumor size and evaluated liver and kidney health using haematoxylin and eosin (H&E) staining. Using Gene Expression Omnibus (GEO) Dataset (GSE201309), we evaluated the relationship between the effects of matrine on malignant tumor cells and ferroptosis. In vitro, tetrazolium-based colorimetric (MTT), lactate dehydrogenase (LDH) and colony formation assays were used to study the effects of matrine on SiHa cell activity and cytotoxicity. We assessed ferroptosis-related protein abundance using western blotting and ferroptosis-related indices in cells using confocal immunofluorescence microscopy. The interaction of matrine with a protein linked to ferroptosis was studied using cellular thermal shift assay (CETSA). The effects of matrine on Piezo1 expression were investigated using calcium imaging. We also used Piezo1-specific siRNA to explore the role of Piezo1 in ferroptosis. Matrine administration effectively inhibited tumor growth in a SiHa-derived tumor-bearing mouse model without inducing noticeable harm. The analysis results of GEO data set show matrine-induced effects in tumor cells were indeed involved in the process of ferroptosis. Treatment with matrine resulted in a significant reduction in GPX4 protein levels and a concurrent increase in lipid peroxide and Fe2+ content, suggesting matrine-induced modulation of ferroptosis. Matrine promoted SiHa cell death in vitro, as evidenced by the results of MTT and LDH assays. Cell death coincides with increases in intracellular Fe2+, reactive oxygen species (ROS), and lipid peroxides. Our study also revealed significant upregulation of Piezo1 expression through the action of matrine, whereas transferrin receptor (Tfr) and System Xc- (xCT) expression and interaction remained unaffected. We provided further evidence that matrine induces calcium influx through the Piezo1 channel, thereby potentially influencing ferroptosis. Transfection with Piezo1 siRNA reversed the effects of matrine in SiHa cell. Our findings indicate that matrine exerts a protective effect against cervical cancer by inducing ferroptosis through the activation of Piezo1, but not xCT or Tfr.

Fenton-like nanoparticles capable of H2O2 self-supply and glutathione consumption for chemodynamic and chemotherapy of cancer.

Chemodynamic therapy (CDT) utilizing the Fenton reaction to convert hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (˙OH) has recently drawn extensive interest in tumor treatment. However, the therapeutic efficiency of CDT often suffers from high concentrations of glutathione (GSH), insufficient endogenous H2O2 and inefficient Fenton activity. Herein, a GSH-depleting and H2O2 self-providing nanosystem that can efficiently load copper ions and doxorubicin (DOX) (MSN-Cu2+-DOX) to induce enhanced CDT and chemotherapy is proposed. The results show that MSN-Cu2+-DOX could release Cu2+ and DOX under acidic conditions. Particularly, both the released Cu2+ and Cu2+ in MSN-Cu2+-DOX are available for ˙OH production via a Fenton-like reaction for CDT. Meanwhile, Cu2+ undergoes a reduction to Cu+ by depleting overexpressed GSH, thereby enhancing CDT. Moreover, the released DOX could not only be used for chemotherapy, but also promote the generation of endogenous H2O2 to improve the efficiency of a Cu-based Fenton-like reaction. Resultantly, this nanosystem featuring Fenton-like activity, GSH consumption, H2O2 self-sufficiency and chemotherapy exhibits a great antitumor effect with a tumor inhibition ratio of 93.05%. Overall, this study provides a promising strategy to enhance CDT for effective tumor therapy.