While nanozymes hold transformative potential for cancer therapy, their clinical translation is hindered by suboptimal catalytic efficiency, poor intratumoral accumulation, and the resilient redox homeostasis of the hypoxic tumor microenvironment (TME). Here, we report an actively targeted, macrophage-based microrobot platform, encapsulating cinnamaldehyde (CA) and glucose oxidase (GOx) alongside biodegradable molybdenum-platinum (Mo-Pt) core-shell nanozymes, to circumvent these barriers. Leveraging the intrinsic chemotaxis of macrophages and a 'Trojan Horse' strategy, this system achieves superior tumor-targeted delivery. The microrobots orchestrate a four-enzyme cascade (catalase-, peroxidase-, glutathione peroxidase-, and GOx-like activities) to synergistically elevate reactive oxygen species levels while depleting glucose and glutathione. This biocatalytic activity is further amplified by extrinsic ultrasound and laser irradiation. In vivo RNA sequencing confirms that this multi-pronged intervention alleviates hypoxia and remodels the TME, leading to potent therapeutic outcomes in laryngeal carcinoma models. Our findings present a versatile microrobotic approach for the precision treatment of recalcitrant solid tumors through stimuli-enhanced metabolic and redox modulation.

[This corrects the article DOI: 10.7150/thno.108875.].

Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia and associated complications such as cardiovascular disease, nephropathy, retinopathy, neuropathy, and chronic non-healing wounds. Current antidiabetic therapies offer only partial glycemic control and are limited by poor bioavailability, adverse effects, and an inability to prevent disease progression. Plant-derived exosome-like nanoparticles (PENPs) have emerged as a promising class of natural nanocarriers with excellent biocompatibility, low immunogenicity, and intrinsic multi-component bioactivity. However, few reviews have addressed recent progress in PENPs for DM therapy. To capture the recent developments in this area, this review provides a systematic synthesis of recent advances in PENPs for DM therapy, covering plant sources, extraction and purification methods, molecular compositions, and therapeutic mechanisms. Preclinical studies have demonstrated that PENPs can improve hyperglycemia, enhance insulin sensitivity, regulate hepatic lipid metabolism, and promote wound healing by modulating oxidative stress, inflammation, gut microbiota, glucose metabolism, and insulin signaling. Additionally, PENPs have been shown to promote angiogenesis via glycolytic reprogramming. Despite these promising findings, challenges including scalable isolation, standardized physicochemical characterization, and clinical translation remain. Future directions include engineering multifunctional PENPs, establishing Good Manufacturing Practice (GMP)-compliant production, and conducting clinical trials to facilitate their integration into precision therapeutics for diabetes management.

Metabolic reprogramming enables tumor cells to survive and proliferate in a nutrient-deficient environment. However, the immunosuppressive tumor microenvironment caused by metabolic reprogramming is often overlooked in current metabolism interventions. Herein, we developed a mito-specific "Trojan Horse" nanoplatform (2-pN@LNPs) coloaded with Niclosamide (Nic) and 2-deoxy-d-glucose (2-DG) to attack key metabolism pathways and synergistically ignite pyroptosis for restoring antitumor immunity. 2-pN@LNPs promoted proton influx across the inner mitochondrial membrane and caused oxidative phosphorylation (OXPHOS) into a futile cycle. Furthermore, 2-pN@LNPs exploited the increased glucose demand to deliver the glycolysis inhibitor 2-DG, causing metabolic network collapse. Both cell and three-dimensional multicellular tumor spheroid results demonstrated superior synergistic metabolic intervention efficacy. The multipath metabolism deprivation leads to irreversible mitochondrial dysfunction, followed by excessive reactive oxygen species accumulation, severe adenosine triphosphate loss, and ultimately exerted a pyroptosis-like micromorphology. Moreover, the synergistic treatment regimen can promote cytotoxic and helper T cells (CD8+/CD4+ T cells) recruitment and M1-type macrophage polarization, facilitating the establishment of a boost in immunological memory to prevent recurrence and metastasis. Overall, this work provides a robust strategy targeting metabolism through mitochondrial uncoupling and glycolysis inhibition, which can effectively improve the antitumor effect, inhibit lung metastasis, and help modulate antitumor immunity.

Hectorite is trioctahedral clay mineral that possess unique characteristics of surface reactivity and adsorption, cation exchange capacity and easy delamination in water into individual nano layers. Thus, hectorite can be a promising nanocarrier with biocompatibility, high payload and controlled release of drug. Therefore, in the present study, hectorite has been used for the delivery of two hydrophobic molecules; chemotherapeutic drug DDP [Cis-diamminedichloroplatinum (II)] and natural photosensitizer hypocrellin A (HA) for combinatorial therapy. The experimental results has been fitted to l -type (Langmuir) adsorption isotherm. The adsorption isotherm showed higher affinity of DDP toward the hectorite with almost comparable CEC value of initial silicate layer of hectorite. The loading of drug into nanoclay was further characterize by using SEM, FTIR, XRD, DLS and TGA, which suggest the presence of DDP molecules in between the interparticle and photosensitizer on the surface of nanoclay. After, adsorption the characteristic properties such as photostability and photobleaching of HA has been significantly improved. The photobleaching efficiencies of free HA and Ht-DDP-HA was 72.8 and 55.2%, respectively, and the 1 O 2 generation quantum yield was 0.86. The in vitro release rate is twofold higher in the presence of laser light and ultrasonic waves. The drug release profile was found to be best fitted by Higuchi square root model, which implicate that release of drug from matrix as square root of time-dependent process and diffusion controlled. The in vitro efficacy of Ht-DDP-HA showed the potent anti-cancerous ability due to combinatorial effect by 2.01 and 1.69 fold times higher efficacy than free DDP and HA, respectively. Flow cytometry data shows the synergistic effect of combined therapy by showing maximum apoptotic and necrotic percentage.

Developing nanozymes for cancer therapy has attracted great attention from researchers. However, enzymes-loaded magnetic particles triggered by both a low-frequency vibrating magnetic field (VMF) and laser for inhibiting tumor growth have never been reported. Herein, we developed a magnetic nanozyme with 3D flower-like nanostructures for cancer therapy. Specifically, the flower-like nanozymes exposed to a VMF could efficiently damage the mitochondrial membrane and cell structure, and inhibit tumor growth through magneto-mechanical force. In parallel, magnetic nanozymes in a weak acid environment containing glucose could generate abundant hydrogen peroxide through glucose oxidase-catalyzed oxidation of glucose, and further significantly promote the Fenton reaction. Interestingly, both glucose oxidase- and Fenton-based catalytic reactions were significantly promoted by the VMF exposure. Flower-like magnetic nanospheres upon a near-infrared laser irradiation could also damage cancer cells and tumor tissues through photothermal effect. The cell-killing efficiency of magnetic nanozymes triggered by the VMF or laser significantly increased in comparison with that of nanozymes without exposures. Mouse tumors grown after injection with magnetic nanozymes was inhibited in a significant way or the tumors disappeared after exposure to a VMF and laser due to the synergistic effect of four major stimuli, viz., magneto-mechanical force, photothermal conversion, improved Fenton reaction, and intratumoral glucose consumption-based starvation effect. This is a great platform that may be suitable for treating many solid tumors.

Nicotinamide adenine dinucleotide (NAD+/NADH) pools homeostasis is recognized as an Achilles’ Heel in tumor metabolism reprogramming. However, mitochondria can enable cancer cells to overcome NADH exhaustion by providing NAD+ precursors and/or intermediates, thus promoting their survival rate and potentially driving uncontrollable proliferation. Here, a synergistic intervention NAD+/NADH homeostasis and mitochondrial metabolism strategy with magnetic resonance imaging (MRI)/photoacoustic imaging (PAI) are developed to address grand challenge of metabolic reprogramming for antitumor bioenergetic therapy. A mitochondrial-targeted cascade amplification nanoplatform ([β-MQ]TRL), triggered by NAD(P)H: quinone oxidoreductase-1 (NQO1), can enable a continuous depletion of cytosol NADH until cell death. The end-product, hydrogen peroxide (H2O2), can be further catalytically converted to higher toxic ·OH in proximity to mitochondria based on [β-MQ]TRL mediated Fenton-like reaction, hijacking tumorigenic energy sources and leading to mitochondrial dysfunction. Additionally, the mild thermal ablation enabled by [β-MQ]TRL further amplifies this cascade reaction to effectively prevent tumor metastasis and recurrence. This synchronous intervention strategy with MRI/PAI establishes unprecedented efficiency in antitumor bioenergetic therapy in vivo, which shows excellent promise for clinical application.

Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug. The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance. ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC. These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK—TGFβ, Hedgehog axis.