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[Display omitted] Chemodynamic therapy (CDT) and photothermal therapy (PTT) have both demonstrated considerable efficacy in the tumor treatment individually, owing to their non-invasive nature and excellent selectivity. However, due to the propensity of tumors for metastasis and recurrence, a singular therapeutic approach falls short of achieving optimal treatment outcomes. Polydopamine (PDA) has excellent photothermal conversion ability and polyoxometalates (POMs) possess diverse enzymatic activities. Here, we synthesized PDA@POM nanospheres comprising polydopamine-coated Tungsten-based polyoxometalate (W-POM). These nanospheres leverage dual enzymatic activities that synergistically enhance both chemodynamic and photothermal therapies for tumor treatment. The PDA-mediated PTT effect enables precise tumor cell destruction, while the W-POM nanozymes catalyzes the generation of highly toxic reactive oxygen species (ROS) from hydrogen peroxide within tumor cells through a Fenton-like reaction, which mitigates tumor hypoxia and induces tumor cell death. This synergistic photothermal catalytic therapy shows enhanced efficacy in tumor suppression, providing a promising new approach for tumor treatment. [ABSTRACT FROM AUTHOR]

[Display omitted] The combination of chemodynamic therapy (CDT) with photothermal therapy (PTT) is a promising approach to enhance antitumor efficacy of chemotherapeutics. In this paper, we developed novel copper-chelated polydopamine (PDA) nanoparticles (NPs) functionalized with hyaluronic acid (HA) (Cu-PDA-HA NPs) to induce apoptosis and cuproptosis-induced cell death, synergistically combining PTT and CDT. Experimental results revealed that Cu-PDA-HA NPs can respond to excessive glutathione (GSH) and hydrogen peroxide (H 2 O 2) in the tumor microenvironment (TME), which will enable their specific degradation, thereby leading to efficient accumulation of Cu2+ within tumor cells. The released Cu2+ ions were reduced by GSH to generate Cu+, which catalyzed in situ Fenton-like reactions to produce cytotoxic hydroxyl radicals (·OH), disrupting cellular redox homeostasis and promoting apoptosis-related CDT. Meanwhile, the photothermal effect of the Cu-PDA-HA NPs could enhance oxidative stress within the tumor by elevating the temperature and subsequent ·OH production. The enhanced oxidative stress made tumor cells more vulnerable to cuproptosis-induced toxicity. Furthermore, in vivo experiments demonstrated that Cu-PDA-HA NPs can still undergo a temperature increase of 18.9°C following 808 nm near-infrared irradiation (1.0 W/cm2, 5 min). Meanwhile, Cu-PDA-HA NPs were able to induce oligomerization of dihydrolipoamide S-acetyltransferase (DLAT) and down-regulate Fe-S cluster proteins such as ferredoxin (FDX1), thereby activating cuproptosis. Therefore, this study provides a novel approach for designing multifunctional nanoparticles with on-demand Cu2+ release and offers a fresh perspective for exploring synergistic therapeutic strategies involving CDT/PTT/apoptosis/cuproptosis. [ABSTRACT FROM AUTHOR]

Abstract Cancer therapy continues to face critical challenges, including drug resistance, recurrence, and severe side effects, which often compromise patient outcomes and quality of life. Exploring novel, cost-effective approaches, this review highlights the potential of Piper nigrum (black pepper) extract (PNE) as a complementary anticancer agent. Piper nigrum, a widely available spice with a rich history in traditional medicine, contains bioactive compounds such as piperine, which have demonstrated significant anticancer activities including cell cycle arrest, apoptosis induction, and inhibition of tumor growth and metastasis. The review evaluates the recent findings from in vitro, in vivo, and clinical studies, emphasizing PNE's capacity to enhance the efficacy of conventional chemotherapeutic agents while mitigating their side effects. Key mechanisms underlying these effects include oxidative stress modulation, suppression of pro-metastatic factors, and synergistic interactions with established drugs like doxorubicin and paclitaxel. These interactions suggest that PNE could play a pivotal role in overcoming chemoresistance and improving therapeutic outcomes. Furthermore, this review highlights the potential benefits of PNE in resource-limited settings, where the cost of cancer treatments often restricts access. However, challenges such as compositional variability, limited bioavailability, and the need for standardization and clinical validation need to be addressed to advance the integration of PNE into basic oncology. By providing a comprehensive analysis of the anticancer mechanisms of PNE and its potential as a cost-effective adjuvant therapy, this review provides new insight into the exploitation of Piper nigrum to improve cancer treatment efficacy while reducing side effects. Future research directions are discussed to address current limitations and facilitate clinical translation.

Apoptotic resistance of tumor often leads to poor efficacy from mono-therapy based on apoptosis. Cuproptosis, a new type of non-apoptotic cell death related to mitochondrial dysfunction, can alter metabolism and enhance ferroptosis, providing a promising strategy for effective synergistic cancer treatment. In this work, Cu0-based nanoparticles (denoted as HA-ZCu) were successfully developed to improve anti-tumor efficacy by combining cuproptosis with enhanced ferroptosis, which was achieved by cuproptosis-induced glutathione synthesis disorder. In vitro studies revealed that HA-ZCu effectively induced cuproptosis and ferroptosis in HepG2 cells. Moreover, HA-ZCu induced mitochondrial dysfunction and decreased intracellular adenosine triphosphate (ATP), glutamate, and glutathione, demonstrating the effective synergy. In vivo studies further approved the synergistic therapeutic efficacy of HA-ZCu, where the inhibition rate of tumor growth reached 83.2 %. This work represents the first example of enhanced anti-tumor efficacy via cuproptosis and ferroptosis synergy through cuproptosis-induced glutathione synthesis disorder. • Utilizing metabolite altered caused by cuproptosis to enhance ferroptosis treatment. • Providing an innovative strategy for synergistic cuproptosis and ferroptosis cancer therapy. • Fabricating novel Cu0-based nanoparticles for synergistic cancer therapy. [ABSTRACT FROM AUTHOR]

The prevalence of Alzheimer's disease (AD) is increasing globally due to population aging. However, effective clinical treatment strategies for AD still remain elusive. The mechanisms underlying AD onset and the interplay between its pathological factors have so far been unclear. Evidence indicates that AD progression is ultimately driven by neuronal loss, which in turn is caused by neuroapoptosis and neuroinflammation. Therefore, the inhibition of neuroapoptosis and neuroinflammation could be a useful anti-AD strategy. Nonetheless, the delivery of active drug agents into the brain parenchyma is hindered by the blood-brain barrier (BBB). To address this challenge, we fabricated a black phosphorus nanosheet (BP)-based methylene blue (MB) delivery system (BP-MB) for AD therapy. After confirming the successful preparation of BP-MB, we proved that its BBB-crossing ability was enhanced under near-infrared light irradiation. In vitro pharmacodynamics analysis revealed that BP and MB could synergistically scavenge excessive reactive oxygen species (ROS) in okadaic acid (OA)-treated PC12 cells and lipopolysaccharide (LPS)-treated BV2 cells, thus efficiently reversing neuroapoptosis and neuroinflammation. To study in vivo pharmacodynamics, we established a mouse model of AD mice, and behavioral tests confirmed that BP-MB treatment could successfully improve cognitive function in these animals. Notably, the results of pathological evaluation were consistent with those of the in vitro assays. The findings demonstrated that BP-MB could scavenge excessive ROS and inhibit Tau hyperphosphorylation, thereby alleviating downstream neuroapoptosis and regulating the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Overall, this study highlights the therapeutic potential of a smart nanomedicine with the capability of reversing neuroapoptosis and neuroinflammation for AD treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

In situ activation of prodrugs or photosensitizers is a promising strategy for specifically killing tumor cells while avoiding toxic side effects. Herein, we originally develop a bioorthogonally activatable prodrug and pro-photosensitizer system to synchronously yield an aggregation-induced emission (AIE) photosensitizer and a chemotherapeutic drug for synergistic chemo-photodynamic-immunotherapy of tumors. By employing molecular engineering strategy, we rationally design a family of tetrazine-functionalized tetraphenylene-based photosensitizers, one of which (named TzPS5) exhibits a high turn-on ratio, a NIR emission, a typical AIE character, and an excellent ROS generation efficiency upon bioorthogonal-activation. With the aid of integrin- or mitochondria-pretargeting, TzPS5 is successfully applied for highly effective PDT ablation of cancer cells both in vitro and in vivo. On this basis, tumor-targeting TzPS5 (TzPS5-cRGD) is constructed and used jointly with a bioorthogonal prodrug, DOX-TCO, and the two are mutually activated to induce cooperative and tumor-specific PDT and chemotherapy, resulting in amplified therapeutic outcomes and improved biosafeties. Moreover, this combination modality elicits robust immunogenic cell death, stimulates systemic antitumor immunity, thereby suppressing both primary and distant tumors, and blocking the pulmonary tumor metastasis. This work is expected to provide a useful guidance for the rational design of activatable phototheranostic agents, and offer a new strategy for co-activation of prodrugs/pro-photosensitizers to boost synergistic antitumor chemo-photodynamic-immunotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Photo-triggered ROS-responsive supramolecular nanoprodrugs (BNN6@GBTC NPs) are constructed via supramolecular self-assembly of amphiphilic prodrug molecule (GBTC) and NO donor (BNN6). BNN6@GBTC NPs possess good stability, ROS responsiveness, and selective HepG2 cells targetability via overexpressed galactose receptors on the cell membrane. When BNN6@GBTC NPs are taken up by HepG2 cells, they can generate ROS upon light irradiation, which can not only be used for photodynamic therapy, but also cleave the thioketal linkage to release camptothecin for chemotherapy. Meanwhile, BNN6 triggering release NO for gas therapy. BNN6@GBTC NPs enable targeted and synergistic chemo/photodynamic/gas therapy, which results in reduced damage to normal cells and enhanced anti-cancer efficacy in vitro. This work provides a novel approach for the design of nanoprodrugs based on supramolecular self-assembly to achieve the multimodal synergistic anti-cancer therapy., (© 2024 Wiley-VCH GmbH.)

Malignant tumors have been a serious threat to human health with their increasing incidence. Difficulties with conventional treatments are toxicity, drug resistance, and recurrence. For this reason, non-invasive treatment modalities such as photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and others have received much attention. Among them, Ferrocene (Fc)-based nanomedicines for enhanced Chemodynamic Therapy (ECDT) is a new therapeutic strategy based on the Fenton reaction. Based on ferrocene's good biocompatibility, potentiation in medicinal chemistry, and good stability of divalent iron ions, scientists are increasingly using it as a Fenton's iron donor for tumor therapy. Such ferrocene-based ECDT nanoplatforms have shown remarkable promise for clinical applications and have significantly increased the efficacy of CDT treatment. Ferrocene-based nanomedicines exhibit exceptional consistency owing to their low toxicity, high stability, enhanced bioavailability, and a multitude of advantages over conventional approaches to cancer treatment. As a consequence, a number of tactics have been investigated in recent years to raise the effectiveness of ferrocene-based ECDT. In this review, we detail the different forms and strategies used to enhance Ferrocene-based ECDT efficiency., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)