Bioactive Layered Double Hydroxides for Synergistic Sonodynamic/Cuproptosis Anticancer Therapy with Elicitation of the Immune Response.

Sonodynamic therapy (SDT) has promising application prospects in tumor therapy. However, SDT does not eradicate metastatic tumors. Herein, Cu-substituted ZnAl ternary layered double hydroxide nanosheets (ZCA NSs) were developed as both sonosensitizers and copper nanocarriers for synergistic SDT/cuproptosis cancer therapy. An optimized electronic structure more conducive to the sonodynamic process was obtained from ZCA NSs via the Jahn-Teller effect induced by the introduction of Cu2+, and the synthesized ZCA NSs regulated the intricate tumor microenvironment (TME) by depleting endogenous glutathione (GSH) to amplify oxidative stress for further enhanced SDT performance. Furthermore, cuproptosis was evoked by intracellular overload of Cu2+ and amplified by SDT, leading to irreversible proteotoxicity. In vitro results showed that such synergetic SDT/cuproptosis triggered immunogenic cell death (ICD) and promoted the maturation of dendritic cells (DCs). Furthermore, the as-synthesized ZCA NS-mediated SDT/cuproptosis thoroughly eradicated the in vivo solid tumors and simultaneously elicited antitumor immunity to suppress lung and liver metastasis. Overall, this work established a nanoplatform for synergistic SDT/cuproptosis with a satisfactory antitumor immunity.

Extracellular fibrin promotes non-small cell lung cancer progression through integrin ß1/PTEN/AKT signaling.

The extracellular matrix (ECM) has been strongly correlated with cancer progression in various tumor types. However, the specific mechanisms underlying ECM-associated tumor behaviors remain unclear. In this study, we found an enriched distribution of fibrin in tumor tissues obtained from high-grade non-small cell lung cancer (NSCLC) patients. For further investigation, we established an in vitro 3D culture system using fibrin gel and found that NSCLC cells grown in this system exhibited increased stemness and tumorigenesis. Mechanistically, we demonstrated that fibrin facilitated the activation of the phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) signaling pathway through integrin ß1. Furthermore, we found that blocking integrin ß1 signals enhanced the tumor suppressive effects of chemotherapy, providing a novel approach for clinical therapy for NSCLC.

Oxygen-Deficient Tungsten Oxide (WOx) Nanobelts with pH-Sensitive Degradation for Enhanced Sonodynamic Therapy of Cancer.

The further bioapplications of sonodynamic therapy (SDT) were hindered by the inadequate efficiency and poor degradability of sonosensitizers and the hypoxic tumor microenvironment (TME). Therefore, it is ideal to develop pH-sensitive sonosensitizers that generate abundant reactive oxygen species (ROS) and rapidly degrade in a neutral environment while slowly degrading in an acidic environment to reduce their long-term toxicity. Herein, the defective tungsten oxide nanobelts (WOx NBs) were developed as a type of pH-sensitive and biodegradable sonosensitizers with a high SDT efficiency and low toxicity for enhanced SDT. The defective oxygen sites of WOx NBs could inhibit the recombination of electrons and holes, making WOx NBs promising sonosensitizers that could generate abundant ROS under ultrasound (US) irradiation. Enhanced by the catalase (CAT) that reacted with H2O2 to generate O2, the WOx NBs exhibited better SDT performance against 4T1 cells in both normoxic and hypoxic environments. In addition, the WOx NBs could degrade by releasing protons (H+), resulting in intracellular acidification and inhibited cell motility that further enhanced the therapeutic effects of SDT. Assisted with CAT and ALG for hypoxia refinement and better retention, the WOx NBs enabled effective SDT and antimetastasis against 4T1 tumors in vivo. Most importantly, the WOx NBs could degrade rapidly in normal tissues but slowly in an acidic TME, which was favorable for their fast clearance, without any obvious long-term toxicity. Our work developed defective WOx NBs with a high SDT efficiency and pH-sensitive degradation for enhanced SDT, which extended the biomedical application of tungsten-based nanomaterials and the further development of SDT.

Collagen-targeted tumor-specific transepithelial penetration enhancer mediated intravesical chemoimmunotherapy for non-muscle-invasive bladder cancer.

Intravesical instillation of chemotherapeutics or immune-stimulating agents could reduce the recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of the bladder tumors. Its efficacy, however, remains to be improved due to the bladder epithelial barrier. Although certain transmucosal delivery carriers are able to enhance the transepithelial penetration of intravesical agents, they could hardly differentiate carcinoma and adjacent normal tissues of the bladder wall. Here, we reported polyethylene glycol (PEG) & glutaraldehyde co-modified fluorinated chitosan (PGFCS) as a collagen-targeted transepithelial penetration enhancer, which could create a tumor-targeted adhesive interface by the aldehyde-selective reaction with collagen amines enriched in the tumor, thus opening the transepithelial-delivery barrier at the tumor site though the fluorinated-chitosan-mediated tight junction regulation. Interestingly, with the help of PGFCS pre-treatment, intravesical instillation of chemotherapeutics pirabucin (THP) combined with immune stimulating agent interleukin-12 could trigger potent antitumor chemoimmunotherapeutic responses in destructing orthotopic bladder tumors and inhibiting cancer recurrence. Our work presents a unique type of tumor-specific transepithelial penetration enhancer, which shows great potential for safe and effective intravesical instillation of NMIBC.

Transmucosal Delivery of Self-Assembling Photosensitizer-Nitazoxanide Nanocomplexes with Fluorinated Chitosan for Instillation-Based Photodynamic Therapy of Orthotopic Bladder Tumors.

Theoretically, on account of improved local bioavailability of photosensitizers and attenuated systemic phototoxicity, intravesical instillation-based photodynamic therapy (PDT) for bladder cancer (BCa) would demonstrate significant advantages in comparison with the intravenous route. Actually, the low transmucosal efficiency, hypoxia regulation deficiency, as well as the biosafety risks of intravesical drug agents all have greatly limited the clinical development of instillation-based PDT for BCa. Herein, based on our recent findings on bladder intravesical vectors and photodynamic treatment, we explore and find that the conventional antiparasitic agent nitazoxanide (NTZ) by mixing with chlorine e6 (Ce6) conjugated human serum albumin (HSA), HSA-Ce6, is capable of forming self-assembled HSA-Ce6/NTZ nanoparticles (NPs). Then, the HSA-Ce6/NTZ complexes further fabricate with fluorinated chitosan (FCS), the synthesized transmucosal carrier, to form a biocompatible nanoscale system HSA-Ce6/NTZ/FCS NPs, which exhibit remarkably improved transmucosal delivery and uptake capacities compared with HSA-Ce6/NTZ alone or non-fluorinated HSA-Ce6/NTZ/CS NPs. Meanwhile, due to the metabolic regulation of tumor cells by NTZ, the tumor hypoxia could be efficaciously ameliorated to further favor PDT. This work represents a new photosensitizer nanomedicine formulation for the perfection of PDT performance through the modulation of tumor hypoxia by clinically approved agents. Thus, intravesical instillation of HSA-Ce6/NTZ/FCS NPs with favorable biocompatibility, followed by cystoscope-mediated PDT, could achieve a dramatically improved therapeutic effect to ablate orthotopic bladder tumors.