A pyroptosis proportion tunable nano-modulator for cancer immunotherapy.

Pyroptosis, a form of programmed cell death mediated by gasdermin proteins, holds significant potential in cancer immunotherapy. However, precise control of pyroptosis in cancer cells is essential to avoid biosafety concerns. This study aimed to develop a tumor-targeted and tunable pyroptosis-inducing strategy to enhance antitumor efficacy while minimizing systemic side effects.

Programmable Bacterial Architects Crafting Sonosensitizers for Tumor-Specific Sonodynamic Immunotherapy.

Sonodynamic therapy (SDT) is a non-invasive cancer treatment that uses ultrasound to activate sonosensitizers for selective tumor ablation. With its superior tissue penetration compared to photodynamic therapy, SDT demonstrates the potential to stimulate antitumor immune responses by modulating the tumor microenvironment. However, its clinical application remains limited by poor tumor specificity and suboptimal sonosensitizer accumulation, which reduces efficacy and causes off-target effects.

An epigenetic regulator synergizes with alphavirus-mediated gene therapy via biomimetic delivery for enhanced cancer therapy.

Gene therapy is promising for treating genetic disorders, but faces challenges in treating cancer due to the intricate genetic and immunosuppressive landscape of this disease. Here, we describe a technology combining alphavirus-based gene therapy with an epigenetic regulator via pyroptosis and immune checkpoints to address these challenges. A filamentous actin-mimicking liposomal delivery system, with high fusion efficiency, was developed that encapsulates the Semliki Forest virus (pSFV) DNA vector to deliver p53 and PDL1 scFv DNA, bypassing traditional endocytic barriers to deliver genes with high efficiency via membrane fusion.

Engineered Bacteria Manipulate Cysteine Metabolism to Boost Ferroptosis-Based Pancreatic Ductal Adenocarcinoma Therapy.

Cysteine metabolism is a key determinant of the defense against ferroptosis in pancreatic ductal adenocarcinoma (PDAC). Blocking cysteine metabolism may trigger potent ferroptosis in PDAC cells by generating lipid peroxides during tumor metabolic processes. However, current methods to limit cysteine availability fall short, failing to efficiently block cysteine metabolism due to inadequate tumor targeting and compensatory cysteine sources.

Bypassing Ca Influx for Antimetastasis Photodynamic Therapy via Robust Nucleus-Targeted Near-Infrared Cyanines.

Hypoxia-induced tumor metastasis severely hinders the efficacy of photodynamic therapy (PDT) in cancer treatment. Current strategies predominantly offer palliative suppression of the HIF-1α pathway, emphasizing the urgent need for innovative PDT approaches to prevent metastasis from the outset. Our study revealed that typical PDT triggers an increase in cytoplasmic Ca levels, activating HIF-1α, and that reducing Ca levels can, in turn, mitigate metastasis.

Proton nanomodulators for enhanced Mn-mediated chemodynamic therapy of tumors via HCO regulation.

Background: Mn-mediated chemodynamic therapy (CDT) has been emerged as a promising cancer therapeutic modality that relies heavily on HCO level in the system. Although the physiological buffers (HCO/HCO) provide certain amounts of HCO, the acidity of the tumor microenvironment (TME) would seriously affect the HCO ionic equilibrium (HCO ⇌ H + HCO). As a result, HCO level in the tumor region is actually insufficient to support effective Mn-mediated CDT.

Injectable Autocatalytic Hydrogel Triggers Pyroptosis to Stimulate Anticancer Immune Response for Preventing Postoperative Tumor Recurrence.

Modulating immunosuppression while eliminating residual microscopic tumors is critical for inhibiting the postoperative recurrence of triple-negative breast cancer (TNBC). Although immunotherapy has shown potential in achieving this goal, due to multiple immunosuppression and poor immunogenicity of apoptosis, a satisfactory anti-recurrence effect still faces the challenge. Herein, an injectable hydrogel-encapsulated autocatalytic copper peroxide (CP@Gel) therapeutic platform is designed and combine it with the clinical-grade DNA methyltransferase inhibitor decitabine (DAC) to effectively inhibit TNBC growth and postoperative recurrence via pyroptosis, killing residual cancer cells that bypass apoptosis resistance while also improving immunogenicity and modulating immunosuppression to achieve an intense anti-tumor immune response.

Iron-based metal-organic framework co-loaded with buthionine sulfoximine and oxaliplatin for enhanced cancer chemo-ferrotherapy via sustainable glutathione elimination.

Background: Emerging ferroptosis-driven therapies based on nanotechnology function either by increasing intracellular iron level or suppressing glutathione peroxidase 4 (GPX4) activity. Nevertheless, the therapeutic strategy of simultaneous iron delivery and GPX4 inhibition remains challenging and has significant scope for improvement. Moreover, current nanomedicine studies mainly use disulfide-thiol exchange to deplete glutathione (GSH) for GPX4 inactivation, which is unsatisfactory because of the compensatory effect of continuous GSH synthesis.

Gene Reprogramming Armed Macrophage Membrane-Camouflaged Nanoplatform Enhances Bionic Targeted Drug Delivery to Solid Tumor for Synergistic Therapy.

Efficient drug delivery to solid tumors remains a challenge. HER2-positive (HER2) tumors are an aggressive cancer subtype with a resistance to therapy, high risk of relapse, and poor prognosis. Although nanomedicine technology shows obvious advantages in tumor treatment, its potential clinical translation is still impeded by the unsatisfactory delivery and therapeutic efficacy.

Engineered Macrophages-Based uPA-Scavenger Load Gemcitabine to Prompt Robust Treating Cancer Metastasis.

The majority of cancer patients die of metastasis rather than primary tumors, and most patients may have already completed the cryptic metastatic process at the time of diagnosis, making them intractable for therapeutic intervention. The urokinase-type plasminogen activator (uPA) system is proved to drive cancer metastasis. However, current blocking agents such as uPA inhibitors or antibodies are far from satisfactory due to poor pharmacokinetics and especially have to face multiplex mechanisms of metastasis.

Pyroptosis in inflammatory diseases and cancer.

Pyroptosis is a lytic and inflammatory type of programmed cell death that is usually triggered by inflammasomes and executed by gasdermin proteins. The main characteristics of pyroptosis are cell swelling, membrane perforation, and the release of cell contents. In normal physiology, pyroptosis plays a critical role in host defense against pathogen infection.

Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord.

Conversion of astrocytes into neurons in vivo offers an alternative therapeutic approach for neuronal loss after injury or disease. However, not only the efficiency of the conversion of astrocytes into functional neurons by single Neurog2, but also the conundrum that whether Neurog2-induced neuronal cells (Neurog2-iNs) are further functionally integrated into existing matured neural circuits remains unknown. Here, we adopted the AAV(2/8) delivery system to overexpress single factor Neurog2 into astrocytes and found that the majority of astrocytes were successfully converted into neuronal cells in multiple brain regions, including the midbrain and spinal cord.

Molecular Mechanisms Underlying Ascl1-Mediated Astrocyte-to-Neuron Conversion.

Direct neuronal reprogramming potentially provides valuable sources for cell-based therapies. Proneural gene Ascl1 converts astrocytes into induced neuronal (iN) cells efficiently both in vitro and in vivo. However, the underlying mechanisms are largely unknown.

Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons.

Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons.

In vivo simultaneous transcriptional activation of multiple genes in the brain using CRISPR-dCas9-activator transgenic mice.

Despite rapid progresses in the genome-editing field, in vivo simultaneous overexpression of multiple genes remains challenging. We generated a transgenic mouse using an improved dCas9 system that enables simultaneous and precise in vivo transcriptional activation of multiple genes and long noncoding RNAs in the nervous system. As proof of concept, we were able to use targeted activation of endogenous neurogenic genes in these transgenic mice to directly and efficiently convert astrocytes into functional neurons in vivo.

Ascl1 Converts Dorsal Midbrain Astrocytes into Functional Neurons In Vivo.

In vivo induction of non-neuronal cells into neurons by transcription factors offers potential therapeutic approaches for neural regeneration. Although generation of induced neuronal (iN) cells in vitro and in vivo has been reported, whether iN cells can be fully integrated into existing circuits remains unclear. Here we show that expression of achaete-scute complex homolog-like 1 (Ascl1) alone is sufficient to convert dorsal midbrain astrocytes of mice into functional iN cells in vitro and in vivo.